ORCID Profile
0000-0002-6818-3451
Current Organisations
University of Melbourne
,
Walter and Eliza Hall Institute of Medical Research
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Publisher: Springer Science and Business Media LLC
Date: 05-1975
DOI: 10.1038/255028A0
Abstract: Messenger RNAs from mouse myeloma cells contain N-6-methyl adenosine and novel 5' termini having 7-methy-guanosine in a 5', 5' triphosphate linkage with ribose-methylated nucleosides. Ten common 5'-terminal sequences of the forms m-7-G-5'-PPP-5'-NmpNp and m-7-G-5'-ppp-5'-NmpNmpNp are reported. Structures like this may be a general feature of mRNA in eukaryotes.
Publisher: Springer Science and Business Media LLC
Date: 26-02-2007
Publisher: American Chemical Society (ACS)
Date: 06-09-1977
DOI: 10.1021/BI00637A027
Publisher: Springer Science and Business Media LLC
Date: 29-06-2012
DOI: 10.1038/CDD.2012.84
Publisher: Springer Science and Business Media LLC
Date: 10-1988
DOI: 10.1007/BF00345502
Abstract: Adriamycin-associated nephropathy (AAN) remains poorly understood. We hypothesized that adriamycin affects endothelial progenitor cells (EPCs), leading to impaired regeneration. We analyzed renal hematopoietic stem cells (HSCs) and EPCs in mice with AAN and examined the potential contribution of adoptive transfer of intact EPCs to the repair processes. FACS analyses revealed that populations of HSCs and EPCs were scarcely represented in control kidneys and did not change numerically in kidneys obtained from mice with AAN. The observed defect in engraftment was attributable to the decreased viability and increased senescence of EPCs. Adoptive transfer of intact EPCs improved proteinuria and renal function, with a threefold decrease in mortality. Infusion of EPCs to adriamycin-treated mice reduced plasma levels of interleukin-1alpha and -beta and granulocyte-colony stimulating factor as well as increased the level of vascular endothelial growth factor with concomitant improvement of vascular density and reduction of apoptosis. An additional mechanism of tissue repair is proposed based on tunneling nanotube formation between EPCs and endothelial cells exposed to adriamycin, leading to the multiple rounds of exchange between EPCs and mature cells. In conclusion, AAN is associated with development of EPC incompetence adoptive transfer of intact EPCs blunts morphological and functional manifestations of AAN and the proposed mechanisms of repair by EPCs include direct incorporation into blood vessels, paracrine signaling, and tunneling nanotube renewal of mitochondrial pool in endothelial cells.
Publisher: Elsevier BV
Date: 11-2001
DOI: 10.1016/S1534-5807(01)00083-1
Abstract: Apoptosis is triggered when proapoptotic members of the Bcl-2 protein family bearing only the BH3 association domain bind to Bcl-2 or its homologs and block their antiapoptotic activity. To test whether loss of the BH3-only protein Bim could prevent the cellular attrition caused by Bcl-2 deficiency, we generated mice lacking both genes. Mice without Bcl-2 have a fragile lymphoid system, become runted, turn gray, and succumb to polycystic kidney disease. Concomitant absence of Bim prevented all these disorders. Indeed, loss of even one bim allele restored normal kidney development, growth, and health. These results demonstrate that Bim levels set the threshold for initiation of apoptosis in several tissues and suggest that degenerative diseases might be alleviated by blocking BH3-only proteins.
Publisher: Springer Science and Business Media LLC
Date: 09-2016
Abstract: Inhibition of the apoptosis pathway controlled by opposing members of the Bcl-2 protein family plays a central role in cancer development and resistance to therapy. To investigate how pro-apoptotic Bcl-2 homology domain 3 (BH3)-only proteins impact on acute myeloid leukemia (AML), we generated mixed lineage leukemia ( MLL)-AF9 and MLL-ENL AMLs from BH3-only gene knockout mice. Disease development was not accelerated by loss of Bim, Puma, Noxa, Bmf, or combinations thereof hence these BH3-only proteins are apparently ineffectual as tumor suppressors in this model. We tested the sensitivity of MLL-AF9 AMLs of each genotype in vitro to standard chemotherapeutic drugs and to the proteasome inhibitor bortezomib, with or without the BH3 mimetic ABT-737. Loss of Puma and/or Noxa increased resistance to cytarabine, daunorubicin and etoposide, while loss of Bim protected against cytarabine and loss of Bmf had no impact. ABT-737 increased sensitivity to the genotoxic drugs but was not dependent on any BH3-only protein tested. The AML lines were very sensitive to bortezomib and loss of Noxa conveyed significant resistance. In vivo, several MLL-AF9 AMLs responded well to daunorubicin and this response was highly dependent on Puma and Noxa but not Bim. Combination therapy with ABT-737 provided little added benefit at the daunorubicin dose trialed. Bortezomib also extended survival of AML-bearing mice, albeit less than daunorubicin. In summary, our genetic studies reveal the importance of Puma and Noxa for the action of genotoxics currently used to treat MLL-driven AML and suggest that, while addition of ABT-737-like BH3 mimetics might enhance their efficacy, new Noxa-like BH3 mimetics targeting Mcl-1 might have greater potential.
Publisher: Springer Science and Business Media LLC
Date: 06-1980
DOI: 10.1038/285450A0
Abstract: Deletions spanning portions of the heavy chain constant region (CH) locus in murine plasmacytomas are revealed by hybridization with cloned immunoglobulin DNA molecules. The pattern of deletions suggests that a lymphocyte clone switches expression of CH genes by successive deletions and that the probable CH gene order is 5' mu-gamma 3-gamma 1-gamma 2b-gamma 2a-alpha 3'.
Publisher: Annual Reviews
Date: 04-1988
DOI: 10.1146/ANNUREV.IY.06.040188.000325
Abstract: Replication proteins encoded by nonconjugative plasmids from the hyperthermophilic archaea of the order Sulfolobales show great ersity in amino acid sequence. We have biochemically characterized ORF735, a replication protein from pSSVi, an integrative nonconjugative plasmid from Sulfolobus solfataricus P2. We show that ORF735 is a DNA helicase of superfamily 3. It unwound double-stranded DNA (dsDNA) in a 3'-to-5' direction in the presence of ATP over a wide range of temperatures, from 37 degrees C to 75 degrees C, and possessed DNA-stimulated ATPase activity. ORF735 existed in solution as a salt-stable dimer and was capable of assembling into a salt-sensitive oligomer that was significantly larger than a hexamer in the presence of a alent cation (Mg(2+)) and an adenine nucleotide (ATP, dATP, or ADP) or its analog (ATPgammaS or AMPPNP). Both N-terminal and C-terminal portions of ORF735 (87 and 160 amino acid residues, respectively, in size) were required for protein dimerization but dispensable for the formation of the higher-order oligomer. The protein unwound DNA only as a large oligomer. Yeast two-hybrid and coimmunoprecipitation assays revealed that ORF735 interacted with the noncatalytic subunit of host primase. These findings provide clues to the functional role of ORF735 in pSSVi DNA replication.
Publisher: Elsevier BV
Date: 02-1967
Publisher: Elsevier BV
Date: 08-1977
DOI: 10.1016/0092-8674(77)90292-6
Abstract: The organization of the 18S, 28S and 5.8S rRNA genes in the mouse has been elucidated by mapping with restriction endonucleases Eco RI, Hind III and Bam HI. Ribosomal DNA fragments were detected in electrophoretically fractionated digests of total nuclear DNA by in situ hybridization with radioiodinated rRNAs or with complementary RNA synthesized directly on rRNA templates. A map of the rDNA which includes 13 restriction sites was constructed from the sizes of rDNA fragments and their labeling by different probes The map indicates that the rRNA genes lie within remarkably large units of reiterated DNA, at least 44,000 base pairs long. At least two, and possibly four, classes of repeating unit can be distinguished, the heterogeneity probably residing in the very large nontranscribed spacer region. The 5.8S rRNA gene lies in the transcribed region between the 18S and 28S genes.
Publisher: Springer Science and Business Media LLC
Date: 11-08-2017
DOI: 10.1038/CDD.2017.131
Publisher: American Society of Hematology
Date: 14-08-2014
DOI: 10.1182/BLOOD-2014-04-570770
Abstract: Loss of Bim accelerated the development and increased the incidence of plasmacytomas in Eμ-v-abl transgenic mice. As in multiple myeloma, elevated expression of myc and cyclin D genes was common and p53 deregulation was rare.
Publisher: Proceedings of the National Academy of Sciences
Date: 02-02-2015
Publisher: The Royal Society
Date: 30-08-1994
Abstract: The bcl -2 gene was first discovered by molecular analysis of the 14 18 chromosome translocation which is the hallmark of most cases of human follicular lymphoma. To date, it is unique among proto-oncogenes because, rather than promoting cell proliferation, it fosters cell survival. This review summarizes the impact of constitutive bcl -2 expression on the development and function of lymphocytes as well as their malignant transformation. Expression of a bcl -2 transgene in the B lymphoid compartment profoundly perturbed homeostasis and, depending on the genetic background, predisposed to a severe autoimmune disease resembling human systemic lupus erythematosus. T lymphoid cells from transgenic mice were remarkably resistant to erse cytotoxic agents. Nevertheless, T lymphoid homeostasis was unaffected and tolerance to self was maintained. Expression of high levels of Bcl-2 facilitated the development of B lymphoid tumours but at relatively low frequency and with long latency. Co-expression of myc and bcl -2, on the other hand, promoted the rapid onset of novel tumours which appeared to derive from a lympho-myeloid stem or progenitor cell. Introduction of the bcl -2 transgene into scid mice facilitated the survival and differentiation of pro-B but not pro-T cells, suggesting that a function necessary to supplement or complement the action of Bcl-2 is expressed later in the T than the B lineage. Crosses of the bcl -2 transgenic mice with p53- /- mice have addressed whether loss of p53 function and gain of bcl -2 function are synergistic for lymphoid cell survival.
Publisher: Proceedings of the National Academy of Sciences
Date: 16-11-2018
Publisher: Springer Science and Business Media LLC
Date: 31-03-2016
DOI: 10.1038/SREP23836
Abstract: Most stromal corneal dystrophies are associated with aggregation and deposition of the mutated transforming growth factor-β induced protein (TGFβIp). The 4 th _FAS1 domain of TGFβIp harbors ~80% of the mutations that forms amyloidogenic and non-amyloidogenic aggregates. To understand the mechanism of aggregation and the differences between the amyloidogenic and non-amyloidogenic phenotypes, we expressed the 4 th _FAS1 domains of TGFβIp carrying the mutations R555W (non-amyloidogenic) and H572R (amyloidogenic) along with the wild-type (WT). R555W was more susceptible to acidic pH compared to H572R and displayed varying chemical stabilities with decreasing pH. Thermal denaturation studies at acidic pH showed that while WT did not undergo any conformational transition, the mutants exhibited a clear pH-dependent irreversible conversion from αβ conformation to β-sheet oligomers. The β-oligomers of both mutants were stable at physiological temperature and pH. Electron microscopy and dynamic light scattering studies showed that β-oligomers of H572R were larger compared to R555W. The β-oligomers of both mutants were cytotoxic to primary human corneal stromal fibroblast (pHCSF) cells. The β-oligomers of both mutants exhibit variations in their morphologies, sizes, thermal and chemical stabilities, aggregation patterns and cytotoxicities.
Publisher: Springer Science and Business Media LLC
Date: 24-11-2003
Publisher: Elsevier BV
Date: 08-1983
DOI: 10.1016/0167-5699(83)90024-5
Abstract: Genetic alterations associated with B-lymphocyte neoplasias were the focus of a workshop organized at the Basel Institute for Immunology on 15-17 March 1983 by Fritz Melchers, Michael Potter and Martin Weigert. The role of viruses, chromosomal abnormalities and cellular one genes in the oncogenic process was discussed in relationship to the normal pathway of B-cell development.
Publisher: Springer Science and Business Media LLC
Date: 31-01-2005
Abstract: Deregulation of MYC expression occurs in many haematological malignancies. Previous studies modelling MYC-induced lymphomagenesis in the mouse used transgenic vectors that directed MYC overexpression in a lineage-specific manner. Here, we describe a transgenic mouse strain in which constitutive MYC expression is driven broadly in haemopoiesis by a vector containing regulatory elements of the Vav gene. Healthy young VavP-MYC17 mice had multiple haemopoietic abnormalities, most notably increased size and numbers of B-lymphoid cells, monocytes and megakaryocytes. The mice rapidly developed tumours and, surprisingly, these were exclusively T-cell lymphomas, mostly of mature CD4(+) CD8(-) T cells, a tumour type that is seldom seen in mouse models. To examine tumour development in the absence of the susceptible T cells, we bred VavP-MYC17 mice lacking the Rag1 recombinase. They survived longer and succumbed to tumours of several different haemopoietic cell types: pre-T cells, pro-B cells, macrophages and unusual progenitor cells. Thus, although T-lineage cells have the shortest latent period to transformation, the VavP-MYC17 transgene drives malignant transformation of multiple cell types and VavP-MYC17 mice provide a new model for tumours of multiple haemopoietic lineages.
Publisher: Elsevier BV
Date: 1972
Publisher: Proceedings of the National Academy of Sciences
Date: 11-1990
Abstract: In the murine myelomonocytic leukemia WEHI-3B, proviral insertions have induced expression of the Hox-2.4 homeobox gene and the gene for the myeloid growth factor interleukin 3 (IL-3). To assess their potential oncogenic role, normal bone marrow cells were infected with retroviruses bearing the genes for IL-3 or IL-3 plus Hox-2.4. Unlike the IL-3 virus, the IL-3/Hox-2.4 virus was highly leukemogenic. Infected cells expressing both genes exhibited retarded differentiation in vitro, generated myelomonocytic cell lines, and provoked a rapid, transplantable myeloid leukemia in vivo. The oncogenic action of Hox-2.4 appears to derive from its ability to impede the IL-3-driven terminal differentiation of myeloid cells. The results suggest that homeobox genes can regulate key differentiation processes such as self-renewal capacity and that their inappropriate expression can be oncogenic.
Publisher: Springer Science and Business Media LLC
Date: 12-1984
DOI: 10.1038/312777A0
Abstract: Chromosome translocations in B-lymphoid tumours are providing intriguing insights and puzzles regarding the role of immunoglobulin genes in the activation of the myc oncogene (reviewed in refs 1, 2). The 15 12 translocations found in most murine plasmacytomas and the analogous 8 14 translocation in human Burkitt's lymphomas involve scissions of murine chromosome 15 (human chromosome 8) near the 5' end of the c-myc gene and subsequent fusion near an immunoglobulin heavy-chain gene. The less well characterized 'variant' translocations found in about 15% of such tumours also involve the myc-bearing chromosome band, but exchange occurs with a chromosome bearing an immunoglobulin light-chain locus--in mice, the kappa-chain locus bearing chromosome 6 (refs 3-5) and, in man, chromosome 2 (or 22), at the same band at which the kappa (or lambda) locus lies (reviewed in ref. 1). The Burkitt variant translocations involve scissions 3' of c-myc one 8 22 translocation placed the C lambda locus just 3' of c-myc, but usually the chromosome 8 breakpoint is a greater, but unknown, distance away from c-myc, more than 20 kilobases (kb) in one 8 2 translocation involving the C kappa gene. Little is known about the murine 6 15 translocations, although a C kappa gene cloned from one plasmacytoma (PC7183) is linked, via chromosome 12 sequences, to an unidentified region of chromosome 15 (ref. 11). We describe here the chromosome fusion region from plasmacytoma ABPC4, which displays the typical reciprocal 6 translocations. We find that the chromosome 6 breakpoint is near C kappa but, unlike those in the heavy-chain locus, not at a position where immunoglobulin genes normally recombine. Moreover, the chromosome 15 sequences involved in the ABPC4 translocation are not derived from the vicinity of c-myc.
Publisher: Proceedings of the National Academy of Sciences
Date: 18-07-2011
Abstract: During immune responses, neutrophils must integrate survival and death signals from multiple sources to regulate their lifespan. Signals that activate either the Bcl-2- or death receptor-regulated apoptosis pathways can provide powerful stimuli for neutrophils to undergo cell death, but whether they act cooperatively in parallel or directly cross-talk in neutrophils is not known. Previous studies suggested that Bcl-2 family proteins are not required for Fas-induced cell death in neutrophils, but did not examine whether they could modulate its rapid onset. By monitoring the rate of change in neutrophil viability associated with activation of the Fas-triggered death receptor pathway using real-time cell imaging, we show that the Bcl-2-related proteins Bid, Bax, and Bak accelerate neutrophil apoptosis but are not essential for cell death. Increased Bcl-2 or Mcl-1 expression prevents efficient induction of apoptosis by Fas stimulation indicating that the Bcl-2-regulated apoptosis pathway can directly interfere with Fas-triggered apoptosis. Fas has been shown to initiate NFκB activation and gene transcription in cell lines, however gene transcription is not altered in Fas-activated Bid −/− neutrophils, indicating that apoptosis occurs independently of gene transcription in neutrophils. The specification of kinetics of neutrophil apoptosis by Bid impacts on the magnitude of neutrophil IL-1β production, implicating a functional role for the Bcl-2-regulated pathway in controlling neutrophil responses to FasL. These data demonstrate that the intrinsic apoptosis pathway directly controls the kinetics of Fas-triggered apoptosis in neutrophils.
Publisher: Cold Spring Harbor Laboratory
Date: 1999
Publisher: Annual Reviews
Date: 04-1995
DOI: 10.1146/ANNUREV.IY.13.040195.002501
Abstract: The control of cell survival is of central importance in tissues with high cell turnover such as the lymphoid system, and its disruption may be a critical step in tumorigenesis. Genes homologous to bcl-2, the oncogene implicated in human follicular lymphoma, play a key role in regulating physiologic cell death (apoptosis). Bcl-2 and its relatives bcl-x and bax encode intracellular membrane-bound proteins that share homology in three domains with a wider family of viral and cellular proteins. The Bcl-2 and Bcl-x proteins enhance the survival of lymphocytes and other cell types but do not promote their proliferation. High levels of Bax or of a smaller Bcl-x variant antagonize the survival function of Bcl-2. The mechanism by which Bcl-2 promotes cell survival remains unknown, but it appears to require association with Bax. Bcl-2 may combat the action of cysteine proteases thought to trigger apoptosis. Bcl-2 is not essential for embryogenesis or lymphoid development. However, upregulation of Bcl-2 appears to be the normal mechanism for positive selection of developing lymphocytes, and its continued expression is critical for survival of mature peripheral B and T cells. Constitutive expression of Bcl-2 does not abrogate deletion of self-reactive lymphocytes, nor disturb T lymphoid homeostasis however, it substantially increases the pool of mature noncycling B cells. The risk of B lymphoid tumors is also enhanced, probably because Bcl-2 can countermand the apoptotic action of other oncoproteins such as Myc. Expression in tumors of bcl-2 and other cell survival genes may constitute a major barrier to the success of genotoxic cancer therapy.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 21-09-2001
Publisher: Springer Science and Business Media LLC
Date: 03-2001
Abstract: Expression of bcl-w, a close relative of bcl-2 is essential for male fertility in mice. Although the initial wave of spermatogenesis in bcl-w -/- mice proceeds normally until 3-4 weeks of age, adults fail to produce sperm. To clarify why bcl-w is essential for adult but not juvenile spermatogenesis, we investigated the expression pattern of eight bcl-2 family members. We found that both the level and pattern of expression varied in different cell types during juvenile and adult spermatogenesis. Anti-apoptotic genes bcl-w, bcl-2 and bcl-xL were all expressed in spermatogonia during juvenile spermatogenesis, but only bcl-w was detected in spermatogonia of adult mice. A similar shift was evident in Sertoli cells. This developmental regulation may co-ordinate physiological germ cell apoptosis in wild type mice and account for the time of onset for pathological germ cell apoptosis in bcl-w -/- animals.
Publisher: Springer Science and Business Media LLC
Date: 14-01-2016
Abstract: This study demonstrates, for the first time, that loss of a single forkhead box class O (FoxO) transcription factor, can promote lymphomagenesis. Using two different mouse models, we show that FoxO3 has a significant tumour-suppressor function in the context of Myc-driven lymphomagenesis. Loss of FoxO3 significantly accelerated myeloid tumorigenesis in vavP- MYC10 transgenic mice and B lymphomagenesis in Eμ- myc transgenic mice. Tumour analysis indicated that the selective pressure for mutation of the p53 pathway during Eμ- myc lymphomagenesis was not altered. Frank tumours were preceded by elevated macrophage numbers in FoxO3 −/− vavP- MYC10 mice but, surprisingly, pre-B-cell numbers were relatively normal in healthy young FoxO3 −/− Eμ- myc mice. In vitro assays revealed enhanced survival capacity of Myc-driven cells lacking FoxO3, but no change in cell cycling was detected. The loss of FoxO3 may also be affecting other tumour-suppressive functions for which FoxO1/4 cannot fully compensate.
Publisher: Springer Science and Business Media LLC
Date: 05-2001
Abstract: Anti-apoptotic members of the Bcl-2 family, such as Bcl-w, maintain cell viability by preventing the activation of the cell death effectors, the caspases. Gene targeting experiments in mice have demonstrated that Bcl-w is required for spermatogenesis and for survival of damaged epithelial cells in the gut. Bcl-w is, however, dispensable for physiological cell death in other tissues. Here we report on the analysis of Bcl-w protein expression using a panel of novel monoclonal antibodies. Bcl-w is found in a erse range of tissues including colon, brain and testes. A survey of transformed cell lines and purified hematopoietic cells demonstrated that Bcl-w is expressed in cells of myeloid, lymphoid and epithelial origin. Subcellular fractionation and confocal laser scanning microscopy demonstrated that Bcl-w protein is associated with intracellular membranes. The implications of these results are discussed in the context of the phenotype of Bcl-w-null mice and recent data that suggest that Bcl-w may play a role in colon carcinogenesis.
Publisher: Proceedings of the National Academy of Sciences
Date: 15-02-1994
Abstract: To explore the role of bcl-2 in T-cell development, a bcl-2 transgene was introduced into mice expressing a T-cell receptor (TCR) transgene encoding reactivity for the mouse male antigen HY presented by the H-2Db class I antigen of the major histocompatibility complex (MHC). Normal thymic development is contingent on the ability of immature thymocytes to interact with self-MHC molecules presented by thymic stroma (positive selection). Thus, thymocyte numbers are low in female anti-HY TCR transgenic mice with a nonselecting (H-2Dd) background. Expression of bcl-2 inhibited the death of nonselectable thymocytes since, strikingly, female H-2Dd bcl-2/TCR transgenic mice developed normal numbers of CD4+CD8+ thymocytes, although these did not mature further into functional T cells. Hence, TCR-MHC interaction may induce positive selection through two signals, one which saves cells from death by increasing Bcl-2 synthesis and another which promotes maturation. Male H-2Db anti-HY TCR transgenic mice normally have a very small thymus, due to deletion of the self-reactive T cells. Expression of bcl-2 reduced the efficiency of deletion, since bcl-2/TCR transgenic male mice accumulated 4- to 6-fold more thymocytes than did TCR transgenic male littermates. Anti-HY TCR-expressing cells were also more numerous in the peripheral lymphoid tissues, but these cells expressed abnormally low levels of CD8 co-receptor and were not responsive to the HY antigen. Thus, although bcl-2 expression h ers the deletion of immature self-reactive cells in the thymus, self-tolerance is maintained.
Publisher: Informa UK Limited
Date: 1989
DOI: 10.1128/MCB.9.1.67
Abstract: Although transgenic mice bearing a c-myc gene controlled by the immunoglobulin heavy-chain enhancer (E mu) eventually develop B-lymphoid tumors, B-lineage cells from preneoplastic bone marrow express the transgene but do not grow autonomously or produce tumors in mice. To determine whether other oncogenes can cooperate with myc to transform B-lineage cells, we compared the in vitro growth and tumorigenicity of normal and E mu-myc bone marrow cells infected with retroviruses bearing the v-H-ras, v-raf, or v-abl oncogene. The v-H-ras and v-raf viruses both generated a rapid polyclonal expansion of E mu-myc pre-B bone marrow cells in liquid culture and 10- to 100-fold more pre-B lymphoid colonies than normal in soft agar. The infected transgenic cells were autonomous, cloned efficiently in agar, and grew as tumors in nude mice. While many pre-B cells from normal marrow could also be induced to proliferate by the v-raf virus, these cells required a stromal feeder layer, did not clone in agar, and were not malignant. Most normal cells stimulated to grow by v-H-ras also cloned poorly in agar, and only rare cells were tumorigenic. With the v-abl virus, no more cells were transformed from E mu-myc than normal marrow and the proportion of tumorigenic pre-B clones was not elevated. These results suggest that both v-H-ras and v-raf, but apparently not v-abl, collaborate with constitutive myc expression to promote autonomous proliferation and tumorigenicity of pre-B lymphoid cells.
Publisher: Springer Science and Business Media LLC
Date: 22-05-2013
DOI: 10.1038/497439C
Publisher: Cold Spring Harbor Laboratory
Date: 2005
Abstract: The Bcl-2 protein family, which largely determines commitment to apoptosis, has central roles in tumorigenesis and chemoresistance. Its three factions of interacting proteins include the BH3-only proteins (e.g., Bim, Puma, Bad, Noxa), which transduce erse cytotoxic signals to the mammalian pro-survival proteins (Bcl-2, Bcl-x(L), Bcl-w, Mcl-1, A-1), whereas Bax and Bak, when freed from pro-survival constraint, provoke the mitochondrial permeabilization that triggers apoptosis. We have discovered unexpected specificity in their interactions. Only Bim and Puma, which mediate multiple cytotoxic signals, engage all the pro-survival proteins. Noxa and Bad instead bind subsets and cooperate in killing, indicating that apoptosis requires neutralization of different pro-survival subsets. Furthermore, Mcl-1 and Bcl-x(L), but not Bcl-2, directly sequester Bak in healthy cells, and Bak is freed only when BH3-only proteins neutralize both its guards. BH3-only proteins such as Bim are tumor suppressors and mediate many of the cytotoxic signals from anticancer agents. Hence, compounds mimicking them may prove valuable for therapy. Indeed, the recently described ABT-737 is a promising "BH3 mimetic" of Bad. We find that, like Bad, ABT-737 kills cells efficiently only if Mcl-1 is absent or down-regulated. Thus, manipulation of apoptosis by targeting the Bcl-2 family has exciting potential for cancer treatment.
Publisher: Research Square Platform LLC
Date: 15-04-2022
DOI: 10.21203/RS.3.RS-1555936/V1
Abstract: The importance of c-MYC in regulating normal lymphopoiesis and promoting lymphomagenesis is well-established, but far less appreciated is the vital supporting role of MYC’s relative MNT. We show here that, during normal T cell development, MNT loss enhances apoptosis and establish the mechanism as elevated expression of the pro-apoptotic BH3-only protein BIM. Using a MYC transgenic mouse model, we also show that MNT loss reduces the pool of premalignant MYC-driven T cells and totally abrogates thymic T lymphomagenesis. Taken together with our recent demonstration that MNT is vital for the survival of MYC-driven premalignant and malignant B lymphoid cells, these results suggest that MNT represents an important new drug target for both T and B lymphoid malignancies.
Publisher: Wiley
Date: 1970
DOI: 10.1111/J.1432-1033.1970.TB00836.X
Abstract: Gaining a better understanding of the molecular circuitries and pathways implicated in the malignant growth and biological behavior of T cell lymphomas may identify potential cellular targets with clinical therapeutic potential. The immunohistochemical characterization of key cellular proteins participating in these pathways can provide surrogate markers of biological activity. The mammalian target of rapamycin complex (mTORC) signaling pathway has been implicated in T-cell lymphopoiesis. The mTORC2 pathway involves downstream activation of nuclear factor (NF)-κB and p-Akt (Ser 473). Fatty acid synthase (FASN) and insulin-like growth factor-1 receptor (IGF-1R) are expressed upstream of the mTORC and NF-κB signaling pathways. Cyclooxygenase (COX)-2 products influence these pathways. Our goal was to use morphoproteomics to characterize the expression patterns of the proteins in various peripheral T-cell lymphomas. Ten cases of peripheral T-cell lymphoma (PTCL) were examined for expression of proteins along the mTORC, Akt and NF-κB pathways and affiliated tumorigenic molecules. These included two angioimmunoblastic PTCL, one natural killer/PTCL, one anaplastic large PTCL, and six PTCL not otherwise specified. Immunostaining for phosphorylated (p) mTOR (Ser 2448), p-Akt (Ser 473), p-NF-κBp65 (Ser 536), IGF-1R (Tyr1165/1166), silent mating type information regulation 2 homolog 1 (Sirt1), COX-2 and FASN was performed on paraffin-embedded tissue for each case. Percent expression was scored using bright-field microscopy with high expression designated as more than 50% of the cells with positive stain in the appropriate subcellular compartment. All ten cases demonstrated nuclear staining for p-mTOR (Ser 2448) corresponding to mTORC 2, and all cases showed strong, diffuse nuclear staining for p-NF-κBp65 (Ser 536). All ten also showed nuclear and cytoplasmic staining for p-Akt (Ser 473) and cytoplasmic staining for IGF-1R. High expressions for nuclear Sirt1, and cytoplasmic COX-2 and FASN were detected in 7, 9, and 8 out of 10 cases, respectively. Six out of 10 cases demonstrated high expression of all the mentioned markers. The constitutive activation of mTORC2, NF-κB, p-Akt and the concomitant expression of IGF-1R suggests convergence of these molecular pathways in T-cell lymphoma. The results of this study also suggest that mTORC2 may be a common denominator among this heterogeneous group of lymphomas. Interference of key nodes of this pathway may carry a clinical therapeutic benefit. Agents that may be considered based on existing data include: bortezomib to inhibit NF-κB pathway activation metformin to inhibit both NF-κB and mTORC2 and histone deacteylase inhibitors to inhibit mTORC2 pathway signaling. Furthermore, panobinostat inhibits Sirt1 pathway when present, and celecoxib inhibits NF-κB pathway activation independent of COX2.
Publisher: Springer Science and Business Media LLC
Date: 31-03-2017
DOI: 10.1038/CDD.2017.30
Publisher: Springer Science and Business Media LLC
Date: 09-2002
DOI: 10.1038/NRC883
Publisher: Proceedings of the National Academy of Sciences
Date: 11-1982
Abstract: A DNA region not associated with conventional immunoglobulin gene rearrangement is rearranged in many lymphoid tumors. This region, designated here as lymphoid rearranging (LyR) DNA, was cloned from plasmacytoma J558 in which it had recombined 5' to a constant (C) region of the alpha heavy (H) chain gene, C alpha, within a switch (S) region, S alpha, involved in the switching of CH genes. Sequence determination established that LyR DNA had recombined within a S alpha recombination unit. LyR DNA does not originate from the H chain locus, and discordance between LyR DNA and CH copy number in certain lines suggests that LyR DNA probably derives from another chromosome. LyR DNA rearrangement is a characteristic of tumors of mature B cells it was detected in 24 of 28 plasmacytomas and B-cell lymphomas, usually as LyR-S alpha, but not in 11 Abelson retrovirus-induced lymphomas of B-cell precursors nor detectably in normal B cells. In contrast, rearrangement was observed in only 3 of 18 T-cell lymphomas, and none of seven nonlymphoid lines. Most tumor lines (49 of 52), whether lymphoid or not, contained a low level of polyadenylylated LyR transcript(s), but several new RNA species with differences in their 5' regions appeared in B-cell lines in which LyR DNA was rearranged, suggesting that rearrangement may activate a new promoter or mode of splicing. The results suggest that the LyR-S alpha rearrangement represents a translocation to chromosome 12 that alters expression of LyR-encoded genes hence, it may have participated in lymphoid tumor oncogenesis.
Publisher: Elsevier BV
Date: 1980
DOI: 10.1016/0092-8674(80)90386-4
Abstract: The organization of mouse immunoglobulin heavy chain genes has been investigated by hybridization with cloned mu and alpha cDNA probes. Restriction endonuclease fragments bearing mu and alpha constant region genes and two types of variable region (VH) genes were compared in BALB/c embryos, liver and nine plasmacytomas synthesizing IgM, IgA, IgG1, IgG2a, IgG2b and IgG3. Embryo DNA was found to contain a single copy of the C mu gene per haploid genome. In contrast, one VH probe (HPC 76) detected at least six related VH genes, while the other (S107) detected a separate set of at least four genes, indicating that the germline contains distinct sets of multiple related VH genes. Most VH genes within the two subsets remained in germline context in different plasmacytomas, providing no evidence for somatic reassortment of VH genes. One plasmacytoma was devoid of specific VH genes, including some related to the expressed VH sequence. This may mean that the translocation event creating an active heavy chain gene involves deletion of the DNA between the expressed VH and CH sequences. The context of C mu sequences in DNA from a plasmacytoma secreting IgM differed from that in embryo DNA, as did C alpha sequences in two IgA- and several IgG-secreting plasmacytomas. Unlike heavy chain expression, rearrangement was not confined to one allele and often took different forms within a single cell line, presumably varying on different homologous chromosomes. Each rearrangement, whether resulting in an active C gene or not, appeared to change sequences upstream but not downstream from the CH gene. Significantly, the eight IgG and IgA plasmacytomas examined had undergone deletions of at least half and often all C mu sequences while retaining the embryo level of C alpha sequences. Hence a deletion mechanism may be responsible for the switch in expression from one CH gene to another which occurs during differentiation of a lymphocyte clone.
Publisher: Springer Science and Business Media LLC
Date: 30-01-1997
Abstract: Apoptosis is the physiological process by which unwanted cells in an organism are killed. Bcl-2, a membrane-bound cytoplasmic protein, is an effective inhibitor of apoptotic cell death induced by many cytotoxic agents. Survival-promoting homologues of Bcl-2 include its close relative, Bcl-xL and the 19 kD protein encoded by the E1B gene of adenoviruses. Whether these proteins are functionally equivalent and whether they can antagonise all or only some pathways to apoptosis is unresolved. We have carried out a systematic comparison of Bcl-2, Bcl-xL and adenovirus E1B19kD activity, using several cell lines and a range of cytotoxic conditions. High levels of expression of each of these proteins inhibited apoptosis induced by growth factor deprivation or treatment with gamma-radiation, glucocorticoid and various cytotoxic drugs. In contrast, none of them could effectively counter apoptosis induced via the TNF receptor or Fas/APO-1 (CD95). Biochemical analysis revealed that all three proteins can associate with Bax and Bak, members of the Bcl-2 protein subfamily that can facilitate apoptosis. The results provide evidence that Bcl-2, Bcl-xL and adenovirus protein E1B19kD are indistinguishable in their ability to regulate the cell death effector machinery.
Publisher: Wiley
Date: 03-1969
DOI: 10.1111/J.1432-1033.1969.TB00521.X
Abstract: [Purpose] The aim of this study was to determine the initial effect of local vibration on the stability of the shoulder joints by applying local vibration to the shoulder joints. [Subjects and Methods] For the test, the subjects held a FlexBar with one hand, at about 10 cm from one end, and performed the oscillation movement with the shoulder at 90° flexion and the elbow in the full-extension position in scaption the vibration stimulus was set to 5 Hz. Then, the subjects underwent the Upper Quarter Y Balance Test to evaluate the stability of the shoulder joints. [Results] The moving distances in the left, right, and upper directions after the oscillation movement were increased significantly compared with the results before the oscillation movement. [Conclusion] A vibration stimulus is effective as an exercise method to increase the stability of the shoulder joints.
Publisher: Proceedings of the National Academy of Sciences
Date: 13-10-1998
Abstract: Proteins of the Bcl-2 family are important regulators of apoptosis in many tissues of the embryo and adult. The recently isolated bcl-w gene encodes a pro-survival member of the Bcl-2 family, which is widely expressed. To explore its physiological role, we have inactivated the bcl-w gene in the mouse by homologous recombination. Mice that lack Bcl-w were viable, healthy, and normal in appearance. Most tissues exhibited typical histology, and hematopoiesis was unaffected, presumably due to redundant function with other pro-survival family members. Although female reproductive function was normal, the males were infertile. The testes developed normally, and the initial, prepubertal wave of spermatogenesis was largely unaffected. The seminiferous tubules of adult males, however, were disorganized, contained numerous apoptotic cells, and produced no mature sperm. Both Sertoli cells and germ cells of all types were reduced in number, the most mature germ cells being the most severely depleted. The bcl-w −/− mouse provides a unique model of failed spermatogenesis in the adult that may be relevant to some cases of human male sterility.
Publisher: Proceedings of the National Academy of Sciences
Date: 09-1979
Abstract: To investigate the organization of immunoglobulin genes, we have constructed a clone library containing 10(6) randomly generated fragments of mouse embryo DNA, corresponding to eight equivalents of the genome. The cloning method involved methylation of embryo DNA at EcoRI recognition sites, partial digestion by EcoRI* endonclease activity, and direct ligation of the resulting large fragments to the lambda phage vector Charon 4A. The library was searched for sequences homologous to a cloned complementary DNA copy of a mu heavy chain mRNA. Nine clones bearing variable heavy chain (VH) sequences were isolated, representing at least eight distinct VH genes. Thus, multiple related VH genes are available in the genome to contribute to immunoglobulin ersity. Each of the two clones carries a pair of VH genes, one pair separated by 15 +/- 1 kilobase pairs of mouse DNA and the other by 14 +/- 2 kilobase pairs. This indicates that related VH genes are clustered and may occur in a tandem array having a repeating unit of 14--16 kilobase pairs. The large spacer sequences between VH genes cannot, however, be highly conserved.
Publisher: Elsevier BV
Date: 2001
DOI: 10.1016/S0968-0004(00)01740-0
Abstract: In response to intracellular damage and certain physiological cues, cells enter the suicide program termed apoptosis, executed by proteases called caspases. Commitment to apoptosis is typically governed by opposing factions of the Bcl-2 family of cytoplasmic proteins. Initiation of the proteolytic cascade requires assembly of certain caspase precursors on a scaffold protein, and the Bcl-2 family determines whether this complex can form. Its pro-survival members can act by sequestering the scaffold protein and/or by preventing the release of apoptogenic molecules from organelles such as mitochondria. Pro-apoptotic family members act as sentinels for cellular damage: cytotoxic signals induce their translocation to the organelles where they bind to their pro-survival relatives, promote organelle damage and trigger apoptosis.
Publisher: Wiley
Date: 23-08-2011
Publisher: Elsevier BV
Date: 06-1999
DOI: 10.1016/S0002-9394(99)00023-9
Abstract: To report acute dacryocystitis with preseptal cellulitis as the presenting sign of leukemia in a child. Case report and literature review. During the initial evaluation of a 17-month-old child with epiphora, left lower eyelid swelling, and a tender left medial canthal mass, a complete blood cell count demonstrated pancytopenia. Bone marrow biopsy disclosed replacement of normal cellular architecture with a dense infiltrate of leukocyte blast forms. DNA analysis disclosed a translocation between chromosome 10 and 11, consistent with the diagnosis of nonlymphocytic leukemia. Although the adjacent lower eyelid cellulitis responded to intravenous antibiotics, lacrimal sac distention decreased only after chemotherapy was initiated. Dacryocystitis with preseptal cellulitis can be a presenting sign of leukemia. This blood malignancy should be considered in patients whose leukocyte counts do not correlate with their clinical presentation.
Publisher: Wiley
Date: 08-1997
Publisher: Elsevier BV
Date: 07-2005
DOI: 10.1016/J.CCR.2005.06.012
Abstract: Impairment of apoptosis, the physiologic cell death process, is central to cancer development and renders tumors refractory to cytotoxic therapy. Bcl-2, the oncoprotein activated in follicular lymphoma, inhibits the conserved cell death pathway triggered by erse cytotoxic agents, as do several close relatives. A small-molecule antagonist of these proteins has now been designed by Oltersdorf et al. Strikingly, ABT-737 sensitizes many tumors to cytotoxic agents and is effective as a single agent against certain lymphomas and solid tumors, provoking stable regression in some tumor xenografts. Hence, this work validates Bcl-2-like proteins as important new targets in cancer therapy.
Publisher: Proceedings of the National Academy of Sciences
Date: 10-1991
Abstract: The biological functions of the BCL2 gene were investigated in transgenic mice harboring human BCL2 cDNA under the control of an immunoglobulin heavy chain enhancer (E mu). Mice of a representative transgenic strain, E mu-bcl-2-22, had a great excess of B lymphocytes, immunoglobulin-secreting cells, and serum immunoglobulins, attributable to increased longevity of B-lineage cells. Pre-B and plasma cells as well as B cells exhibited prolonged survival in culture. Immunized animals produced an lified and protracted antibody response. Within the first year of life, most mice spontaneously produced antibodies to nuclear antigens, and 60% developed kidney disease, diagnosed as immune complex glomerulonephritis. Thus E mu-bcl-2-22 mice constitute a transgenic model for a systemic autoimmune disease resembling the human disorder systemic lupus erythematosus.
Publisher: Springer Science and Business Media LLC
Date: 08-1970
DOI: 10.1038/227570A0
Abstract: ZnO nanorods (NRs) arrays doped with a large concentration of Mn synthesized by aqueous chemical growth and were characterized by SEM, photoluminescence, Raman scattering, magnetic force microscopy (MFM). By comparison of spectra taken on pure and Mn-doped ZnO NRs, a few new Raman impurity-related phonon modes, resulting from the presence of Mn in the investigated s les. We also present a vibrational and magnetic characterization of in idual lying nanorods using Raman and MFM imaging. Confocal scanning micro-Raman mapping of the spatial distribution of intensity and frequency of phonon modes in single Mn-doped ZnO NRs nanorods is presented and analyzed for the first time. Mn-related local vibrational modes are also registered in Raman spectra of the single nanorod, confirming the incorporation of Mn into the ZnO host matrix. At higher Mn concentration the structural transformation toward the spinel phase ZnMn
Publisher: Springer Science and Business Media LLC
Date: 20-09-1999
Abstract: The pathways to lymphoid neoplasia have been explored in a number of transgenic models. Because B lymphoid malignancies often involve translocation of an oncogene (e.g. myc, bcl-2, cyclin D1) to an immunoglobulin locus, resulting in its deregulated expression, the consequences of oncogene overexpression in lymphocytes can be evaluated with transgenes driven by an immunoglobulin regulatory element, such as an enhancer from the IgH locus. Mice bearing such transgenes have provided insight into the preneoplastic state, including alterations in the control of cellular proliferation, differentiation or apoptosis. They have also allowed studies on oncogene cooperation in vivo and the modulating effect of genetic background. Briefly reviewed here are the models studied in the authors' laboratories. Mice bearing myc and bcl-2 transgenes have received most attention but others studied include abl, ras, cyclin D1 and bmi-1 oncogenes. Also discussed is a new transgenic vector that should facilitate transgenic approaches to non-lymphoid leukemias. The vector bears elements from the promoter region of the vav gene, which is expressed almost exclusively in hematopoietic cells. It has proven capable of driving transgene expression throughout the hematopoietic compartment, including progenitor cells and their precursors. This novel vector should aid studies on many aspects of hematopoiesis, including the modeling of leukemogenesis.
Publisher: Elsevier BV
Date: 1999
DOI: 10.1016/S0301-472X(98)00015-0
Abstract: Transduction of hematopoietic stem cells with a novel retrovirus has allowed long-term expression of human Bcl-2 in multiple hematopoietic lineages. Thy-1.2lo Sca-1+ H-2Khi stem cells enriched from the bone marrow of 5-fluorouracil-treated (Ly5-2) mice were infected with the bcl-2 retrovirus and injected into (Ly5-1) irradiated recipients. Analysis at 5 months indicated that reconstitution of hematopoiesis occurred predominantly from donor-derived (Ly5-2+) stem cells and that, in half the mice (18 of 35), most blood cells derived from virally transduced stem cells. The level of Bcl-2 expression achieved with the retroviral vector approached that of a well-characterized transgenic vector and could be sustained for life in several blood cell lineages. In the 25 mice assessed at 10 months, human Bcl-2 was readily detectable in 62+/-22% of Ly5-2+ peripheral blood leukocytes. More detailed analysis of a cohort killed between 14 and 20 months established that human Bcl-2 protein could be detected in B and T lymphocytes, granulocytes, macrophages, and some immature erythroid cells. Furthermore, hematopoietic stem cells from the bone marrow of these mice maintained Bcl-2 expression in hematopoietic tissues of secondary recipients for at least another 19 months. These data provide clear evidence for efficient infection of primitive hematopoietic stem cells and for maintenance of proviral expression for over 2.5 years, the lifespan of mice. The level of exogenous Bcl-2 was sufficient to enhance survival of B and T lymphoid cells, granulocytes, and myeloid colony-forming cells cultured under suboptimal conditions, but hematopoiesis in the mice was not notably perturbed.
Publisher: Springer Science and Business Media LLC
Date: 16-01-2018
Publisher: Wiley
Date: 15-01-1998
Publisher: Elsevier BV
Date: 11-2006
Publisher: Oxford University Press (OUP)
Date: 1990
Abstract: In vitro, murine interleukin 5 (IL-5) acts as a colony-stimulating factor for eosinophils and induces B cells to proliferate and secrete antibody. In order to assess the biological effects of IL-5 in vivo, we transplanted lethally irradiated mice with bone marrow cells infected with a recombinant retrovirus bearing the IL-5 coding sequence. Within 2 weeks the peripheral blood of recipient mice exhibited a marked eosinophilia which persisted for at least 12 months, and an excess number of eosinophils was also evident in the bone marrow, spleen, liver, lung, and gut. Although no changes could be detected in the conventional B lymphocyte population, the peritoneum was replete with B cells characteristic of the Ly-1 lineage. Despite these expanded cell populations, mice remained healthy for 12 months after transplantation. These results suggest that IL-5 acts primarily on eosinophils and B cells of the Ly-1 lineage and that persistent overproduction of these cell types is not pathogenic.
Publisher: Informa UK Limited
Date: 07-1989
DOI: 10.1128/MCB.9.7.2798
Abstract: In chronic myeloid leukemia and some cases of acute lymphoblastic leukemia, a 9 chromosome translocation has fused most of the c-abl oncogene to a gene designated bcr. To explore in vivo the biological effects of the chimeric gene, we introduced a facsimile of the translocation product, a bcr-v-abl gene, into the mouse germ line under the control of the immunoglobulin heavy-chain enhancer or a retroviral long terminal repeat. Some transgenic mice bearing either construct developed clonal lymphoid tumors. T lymphomas predominated, but some pre-B lymphomas developed. The transgenes were expressed in the tumors but not detectably in the lymphoid tissues of nontumorous transgenic animals, implying that transcription is activated by a low-frequency somatic event. These results demonstrate that bcr-v-abl is tumorigenic in vivo and provide a new animal model for lymphomagenesis.
Publisher: Wiley
Date: 15-02-1998
Publisher: Springer Science and Business Media LLC
Date: 24-01-2014
DOI: 10.1038/CDD.2013.201
Publisher: The American Association of Immunologists
Date: 08-2015
Publisher: American Association for the Advancement of Science (AAAS)
Date: 28-08-1998
DOI: 10.1126/SCIENCE.281.5381.1322
Abstract: REVIEW Bcl-2 and related cytoplasmic proteins are key regulators of apoptosis, the cell suicide program critical for development, tissue homeostasis, and protection against pathogens. Those most similar to Bcl-2 promote cell survival by inhibiting adapters needed for activation of the proteases (caspases) that dismantle the cell. More distant relatives instead promote apoptosis, apparently through mechanisms that include displacing the adapters from the pro-survival proteins. Thus, for many but not all apoptotic signals, the balance between these competing activities determines cell fate. Bcl-2 family members are essential for maintenance of major organ systems, and mutations affecting them are implicated in cancer.
Publisher: Elsevier BV
Date: 07-1966
Publisher: Elsevier BV
Date: 11-1991
DOI: 10.1016/0092-8674(91)90362-3
Abstract: Early death is the fate of most developing T lymphocytes. Because bcl-2 can promote cell survival, we tested its impact in mice expressing an E mu-bcl-2 transgene within the T lymphoid compartment. The T cells showed remarkably sustained viability and some spontaneous differentiation in vitro. They also resisted killing by lymphotoxic agents. Although total T cell numbers and the rate of thymic involution were unaltered, the response to immunization was enhanced, consistent with reduced death of activated T cells. No T cells reactive with self-superantigens appeared in the lymph nodes, but an excess was found in the thymus. These observations, together with previous findings on B cells, suggest that modulated bcl-2 expression is a determinant of life and death in normal lymphocytes.
Publisher: Springer Science and Business Media LLC
Date: 12-1975
DOI: 10.1007/BF00357015
Publisher: American Chemical Society (ACS)
Date: 03-1972
DOI: 10.1021/BI00756A006
Abstract: To acquire the ability to recognize and destroy virus and plasmid invaders, prokaryotic CRISPR-Cas systems capture fragments of DNA within the host CRISPR locus. Our results indicate that the process of adaptation by a Type II-A CRISPR-Cas system in Streptococcus thermophilus requires Cas1, Cas2, and Csn2. Surprisingly, we found that Cas9, previously identified as the nuclease responsible for ultimate invader destruction, is also essential for adaptation. Cas9 nuclease activity is dispensable for adaptation. In addition, our studies revealed extensive, unbiased acquisition of the self-targeting host genome sequence by the CRISPR-Cas system that is masked in the presence of active target destruction.
Publisher: Proceedings of the National Academy of Sciences
Date: 1980
Abstract: To elucidate the structure of the gene for the constant region of immunoglobulin mu chains, we have cloned a 9.9-kilobase-pair fragment of mouse DNA bearing a gene for the constant region of the mu chain (C mu gene) from an IgM-secreting mouse plasmacytoma. The sequence around this gene has apparently undergone somatic rearrangement the gene occurs in an EcoRI restriction endonuclease fragment of a different size from that in embryo or liver DNA and no C mu-bearing fragment of embryo size remains in the plasmacytoma. The cloned sequence lacks a variable region gene hence, if this C mu gene is active, its position within the clone indicates that the gene for the variable region of a heavy chain (VH gene) must be more than 3.7 kilobase pairs away. The C mu gene is ided by three intervening sequences into four coding segments, each of which encodes one of the domains (homology units) of the polypeptide. The nucleotide sequence coding for amino acids near the V-C junction is not present within the C mu clone or clones bearing homologous embryonic VH genes. This suggests that an immunoglobulin heavy chain, in common with light chains, is encoded not only by a V and C gene, but also by an independent joining region (JH) gene.
Publisher: Springer Science and Business Media LLC
Date: 03-1974
DOI: 10.1007/BF00309570
Abstract: The aim of the present study was to determine the relative quantitative expression of hypoxia-inducible factor (HIF)-1α, -2α and -3α, and VEGF-A in laryngeal carcinoma. A total of 63 patients with carcinoma of the larynx were enrolled in the study. Total RNA was isolated from fresh, frozen normal and tumor tissues of each patient, and quantitative polymerase chain reaction was performed. HIF-1α was upregulated in the majority of patients (44 patients 69.84%). By contrast, only 7 (11.11%) patients from the whole group displayed HIF-2α overexpression, while the HIF-3α isoform was silenced in the majority of patients (48 patients, 76.19%). A small group of 5 (7.94%) patients exhibited significant overexpression of the HIF-3α isoform. VEGF-A expression was significantly higher (P<0.05) in patients with upregulated HIF-1α (2.72±1.41 RQ) compared with patients without upregulated HIF-1α (1.86±1.46 RQ). There was a moderate positive correlation between mRNA expression levels of HIF-1α and VEGF-A (r
Publisher: Proceedings of the National Academy of Sciences
Date: 05-1980
Abstract: We have used cloned nucleotide sequences as probes to search for immunoglobulin RNA in T and B lymphoid and nonlymphoid tumor cell lines. Polyadenylated RNA from the cells was fractionated electrophoretically by size and fixed to diazobenzyloxymethyl-paper, and then immunoglobulin RNA species were revealed by hybridization with 32P-labeled cloned sequences for mu heavy chain and kappa light chain. kappa mRNA was detected only in B lymphoid lines known to synthesize kappa chains. No mu RNA was detectable in erythroleukemia, mastocytoma, or sarcoma cells. RNA bearing mu constant region (C mu) sequences, however, was detected in four of nine T lymphoma and four of five myeloid tumor cell lines tested, as well as in B lymphoma and "pre-B" Abelson lymphoma cells. In contrast to the single mu RNA species of 2.6 kilobases (kb) in a plasmacytoma, in idual T lymphoma and myeloid lines yielded up to three discrete mu RNA species of apparent size 1.9, 2.2, and 3.0 kb, each different from the two mu RNA species in a B lymphoma line (2.4 and 2.7 kb) or the single species in "pre-B" lymphoma cells (2.9 kb). Both chromosomal complements of the C mu gene in STRij-4 T cells were found to be rearranged from their embryonic (germ line) context. The results suggest that the C mu gene functions not only in T cells, wherein the ability to recognize antigen is long established, but also in myeloid cells.
Publisher: Informa UK Limited
Date: 03-2005
Publisher: Elsevier BV
Date: 02-1993
DOI: 10.1016/0092-8674(93)90111-3
Abstract: In transgenic mice, self-reactive B lymphocytes are eliminated if they encounter membrane-bound self antigens during their development within the bone marrow. We show here that two separate and sequential events, arrested development and cell death, bring about B cell elimination. Developmental arrest is an early outcome of antigen binding in immature B cells, blocks acquisition of adhesion molecules and receptors important for B cell migration and activation, and is rapidly reversible by removal of antigen. Death of the arrested B cells occurs within 1 to 3 days and can be delayed by expression of a bcl-2 transgene, which results in escape of large numbers of self-reactive B cells from the bone marrow but fails to override the developmental arrest. These findings define a novel pathway for B cell elimination, involving an initial stage vulnerable to breakdown in autoimmune disease.
Publisher: National Institute of Industrial Health
Date: 2018
Publisher: Springer Science and Business Media LLC
Date: 04-1985
DOI: 10.1038/314740A0
Abstract: The frequent trisomy of murine chromosome 15 in T lymphomas suggests that it bears one or more genes conducive to T-cell neoplasia. One such gene seems to be c-myc, the oncogene frequently activated in B-lymphoid tumours either by retroviral insertion, as in the avian bursal lymphomas, or by a translocation to the immunoglobulin heavy-chain locus, as in the predominant t(12 15) of murine plasmacytomas and the analogous t(14 8) of human Burkitt lymphomas. The c-myc gene was strongly implicated in T-cell neoplasia when 15-25% of T lymphomas arising in AKR mice, a strain prone to leukaemia, were found to have retroviral inserts near c-myc. Proviruses near c-myc were also found in several T lymphomas induced by murine leukaemia viruses (MuLV) in both mice and rats, but many of the rat thymomas bear an insert instead at one of several other common sites, at least two of which have murine homologues on chromosome 15. We show here that some murine T lymphomas contain proviral inserts in the recently identified chromosome 15 locus for plasmacytoma variant (6 15) translocations, which we have denoted pvt-1. Although 6 15 breakpoints map cytogenetically to the same chromosome band as c-myc, the alterations of pvt-1 in tumours occur at least 72 kilobases (kb) from the c-myc promoters. The insertions in T lymphomas suggest that an altered pvt-1 locus is conducive to neoplasia in T cells as well as B cells, possibly via long-range effects on c-myc expression.
Publisher: Springer Science and Business Media LLC
Date: 08-02-2023
DOI: 10.1038/S41418-023-01119-Y
Abstract: The importance of c-MYC in regulating lymphopoiesis and promoting lymphomagenesis is well-established. Far less appreciated is the vital supporting role of MYC’s relative MNT. Using Rag1Cr e-mediated Mnt deletion in lymphoid progenitor cells, we show here that, during normal T cell development, MNT loss enhances apoptosis, at least in part by elevating expression of the pro-apoptotic BH3-only protein BIM. Moreover, using T lymphoma-prone VavP- MYC transgenic mice, we show that Mnt deletion reduces the pool of pre-malignant MYC-driven T lymphoid cells and abrogates thymic T lymphomagenesis. In addition, we establish that Mnt deletion prevents T lymphoma development in γ-irradiated mice, most likely by enhancing apoptosis of T lymphoid cells repopulating the depleted thymus. Taken together with our recent demonstration that MNT is vital for the survival of MYC-driven pre-malignant and malignant B lymphoid cells, these results suggest that MNT represents an important new drug target for both T and B lymphoid malignancies.
Publisher: Elsevier BV
Date: 10-2007
Publisher: Oxford University Press (OUP)
Date: 1980
Abstract: To investigate the DNA surrounding genes for immunoglobulin heavy chain constant (CH) regions, we have isolated two clones bearing a C gamma 3 gene and two bearing a C gamma 1 gene from a library of mouse embryo DNA fragments. The C gamma 3 clones span 8.6 kilobase pairs (kb) on the 5' side of the gene and 6.7 kb on its 3' side, while the C gamma 1 clones together span 13 kb of 5' flanking sequence and 2.5 kb of 3' flanking sequence. Restriction mapping of the C gamma 3 gene indicates that intervening sequences ide the gene into segments of domain size, as in other CH genes. Hybridization of clone fragments to restriction digests of mouse DNA indicates that both the C gamma 1 and C gamma 3 genes probably occur as single copies in the genome. Moreover, the entire cloned sequences on the 5' side of both genes appear to be unique in the genome, indicating that no large common sequences flank CH genes. Restriction data suggest that the C gamma 3 gene is 37-40 kb 5' to the C gamma 1 gene.
Publisher: Proceedings of the National Academy of Sciences
Date: 04-1983
Abstract: Molecular cloning has recently established that the 15 chromosome translocations in murine plasmacytomas fuse DNA from chromosome 15 to the immunoglobulin heavy (H) chain locus, usually within the switch recombination region near the alpha constant region gene. We show here that the incoming DNA bears the cellular gene (c-myc) homologous to the oncogene (v-myc) of avian retrovirus MC29. In human Burkitt lymphomas bearing an 8 translocation, c-myc was also rearranged, apparently (in at least two cases) to an H chain switch recombination region (mu or alpha), and both products of a reciprocal chromosome exchange were detectable. Both the murine and human c-myc genes contain two exons homologous to v-myc, and additional 5' and 3' murine genomic segments (apparent exons) were defined by hybridization to c-myc mRNAs. In plasmacytomas, chromosome breakpoints fall near or within the 5' exon and apparently disrupt the normal c-myc transcriptional unit, because plasmacytoma c-myc mRNAs differ from the mRNA in lines without c-myc rearrangement. The translocated gene presumably has lost its normal 5' regulatory sequences and may well encode an altered myc polypeptide. We propose that altered expression of the c-myc gene, induced by translocation to an immunoglobulin locus, is a critical oncogenic event for these B lymphoid tumors. Two events may be required, because the plasmacytoma oncogene capable of transforming fibroblasts is not c-myc.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 22-11-1991
Abstract: Numerous cancer-prone strains of mice have been created by the introduction of candidate tumor-promoting genes into fertilized eggs. Each transgenic strain is predisposed to develop specific types of tumors, but they usually arise stochastically because of the need for spontaneous mutation of genes that collaborate with the introduced oncogene. These mice are providing insights into the effects of in idual oncogenes on cellular proliferation, differentiation, and viability, as well as on oncogene cooperativity. Their predisposed state imposes sensitivity to viral and chemical carcinogenesis, and the mice should prove valuable in tests of potential carcinogens, therapies, and preventive measures.
Publisher: American Society of Hematology
Date: 09-12-2010
DOI: 10.1182/BLOOD-2010-04-280818
Abstract: DNA-damaging chemotherapy is the backbone of cancer treatment, although it is not clear how such treatments kill tumor cells. In nontransformed lymphoid cells, the combined loss of 2 proapoptotic p53 target genes, Puma and Noxa, induces as much resistance to DNA damage as loss of p53 itself. In Eμ-Myc lymphomas, however, lack of both Puma and Noxa resulted in no greater drug resistance than lack of Puma alone. A third B-cell lymphoma-2 homology domain (BH)3-only gene, Bim, although not a direct p53 target, was up-regulated in Eμ-Myc lymphomas incurring DNA damage, and knockdown of Bim levels markedly increased the drug resistance of Eμ-Myc/Puma−/−Noxa−/− lymphomas both in vitro and in vivo. Remarkably, c-MYC–driven lymphoma cell lines from Noxa−/−Puma−/−Bim−/− mice were as resistant as those lacking p53. Thus, the combinatorial action of Puma, Noxa, and Bim is critical for optimal apoptotic responses of lymphoma cells to 2 commonly used DNA-damaging chemotherapeutic agents, identifying Bim as an additional biomarker for treatment outcome in the clinic.
Publisher: Elsevier BV
Date: 07-1966
Publisher: Elsevier BV
Date: 12-1976
DOI: 10.1016/0005-2787(76)90228-8
Abstract: The borohydride reaction has been used to investigate modified nucleosides and end groups in purified immunoglobulin light chain mRNA and rabbit globin mRNA. 1. The light chain mRNA was isolated from the microsomal fraction of MOPC 41A mouse myelomas, which secrete kappa chains, by two cycles of oligo(dT) cellulose chromatography and glycerol gradient centrifugation. The 12 S mRNA was active in a Krebs II ascites cell-free system and appeared to be homogenous as judged by gradient centrifugation, polyacrylamide gel electrophoresis in 98% formamide and fingerprint analysis of 125I-labelled mRNA. 2. End group labelling of the light chain and globin mRNAs by oxidation with periodate and reduction with boro[3H]hydride showed that the RNAs have a 5'-terminal 7-methyl guanosine in 5'-pyrophosphate linkage with the next nucleoside. 3. To detect any modified residues in the interior of chains, nucleosides in complete digests of the mRNAs were converted by the borohydride reaction to 3H-labelled nucleoside trialcohols, which were fractionated by two dimensional chromatography (the Randerath technique). The light chain mRNA was found to contain N6-methyl adenosine (1 mole) but the rabbit globin mRNAs lacked this nucleoside. Deficiencies in this technique for analysis of minor constituents in large RNAs were noted.
Publisher: Wiley
Date: 09-1968
Publisher: Wiley
Date: 09-1972
DOI: 10.1111/J.1432-1033.1972.TB02011.X
Abstract: [Purpose] To report the effects of consecutive application of stretching, Schroth, and strengthening exercises in an adult with idiopathic scoliosis. [Subject] A 26-year-old woman with idiopathic scoliosis, Cobb's angle of 20.51°, and back pain. [Methods] The exercise program consisted of 3 sessions: 10 minutes of stretching exercises, 20 minutes of Schroth exercises, and 10 minutes of strengthening exercises. This program was implemented 3 times a week, for 8 weeks. [Results] The thoracic Cobb's angle decreased from 20.51° to 16.35°, and the rib hump decreased from 15° to 9°. [Conclusion] Consecutive application of stretching, Schroth, and strengthening exercises may help reduce Cobb's angle and the rib hump in adults with idiopathic scoliosis.
Publisher: Elsevier BV
Date: 10-1986
DOI: 10.1016/0092-8674(86)90361-2
Abstract: Transgenic mice bearing a c-myc oncogene subjugated to the lymphoid-specific immunoglobulin heavy chain enhancer (E mu) develop clonal B lymphoid malignancies, but most young E mu-myc mice lack malignant clones. Their prelymphomatous state has allowed us to examine how constitutive c-myc expression influences B cell development. We find that early stages are overrepresented, even before birth. Pre-B cells of polyclonal origin increase greatly, while B cells develop in reduced number. Both the pre-B and the B cells appear to be in an active state, since they are larger than normal and a greater fraction are in the cell cycle. Enforced myc expression has thus favored proliferation over maturation. Hence, a normal function of c-myc may be to regulate differentiation as well as to promote cell cycling.
Publisher: Proceedings of the National Academy of Sciences
Date: 17-08-1999
Abstract: The Bcl-2 family of proteins regulates apoptosis, the cell death program triggered by activation of certain proteases (caspases). An attractive model for how Bcl-2 and its closest relatives prevent caspase activation is that they bind to and inactivate an adaptor protein required for procaspase processing. That model has been supported by reports that mammalian prosurvival Bcl-2 relatives bind the adaptor Apaf-1, which activates procaspase-9. However, the in vivo association studies reported here with both overexpressed and endogenous Apaf-1 challenge this notion. Apaf-1 could be immunoprecipitated together with procaspase-9, and the Apaf-1 caspase-recruitment domain was necessary and sufficient for their interaction. Apaf-1 did not bind, however, to any of the six known mammalian prosurvival family members (Bcl-2, Bcl-x L , Bcl-w, A1, Mcl-1, or Boo), or their viral homologs adenovirus E1B 19K and Epstein–Barr virus BHRF-1. Endogenous Apaf-1 also failed to coimmunoprecipitate with endogenous Bcl-2 or Bcl-x L , or with two proapoptotic relatives (Bax and Bim). Moreover, apoptotic stimuli did not induce Apaf-1 to bind to these family members. Thus, the prosurvival Bcl-2 homologs do not appear to act by sequestering Apaf-1 and probably instead constrain its activity indirectly.
Publisher: American Society of Hematology
Date: 28-10-2010
DOI: 10.1182/BLOOD-2010-04-281071
Abstract: Diverse human cancers with poor prognosis, including many lymphoid and myeloid malignancies, exhibit high levels of Mcl-1. To explore the impact of Mcl-1 overexpression on the hematopoietic compartment, we have generated vavP-Mcl-1 transgenic mice. Their lymphoid and myeloid cells displayed increased resistance to a variety of cytotoxic agents. Myelopoiesis was relatively normal, but lymphopoiesis was clearly perturbed, with excess mature B and T cells accumulating. Rather than the follicular lymphomas typical of vavP-BCL-2 mice, aging vavP-Mcl-1 mice were primarily susceptible to lymphomas having the phenotype of a stem rogenitor cell (11 of 30 tumors) or pre-B cell (12 of 30 tumors). Mcl-1 overexpression dramatically accelerated Myc-driven lymphomagenesis. Most vavP-Mcl-1/ Eμ-Myc mice died around birth, and transplantation of blood from bitransgenic E18 embryos into unirradiated mice resulted in stem rogenitor cell tumors. Furthermore, lethally irradiated mice transplanted with E13 fetal liver cells from Mcl-1/Myc bitransgenic mice uniformly died of stem rogenitor cell tumors. When treated in vivo with cyclophosphamide, tumors coexpressing Mcl-1 and Myc transgenes were significantly more resistant than conventional Eμ-Myc lymphomas. Collectively, these results demonstrate that Mcl-1 overexpression renders hematopoietic cells refractory to many cytotoxic insults, perturbs lymphopoiesis and promotes malignant transformation of hematopoietic stem and progenitor cells.
Publisher: Elsevier BV
Date: 04-1984
DOI: 10.1016/0092-8674(84)90047-3
Abstract: The 15 translocations in murine plasmacytomas represent recombination of the myc oncogene with the immunoglobulin CH locus, often within CH switch recombination (SH) regions. Chromosome junctions cloned from four plasmacytomas confirmed that the translocation generates reciprocal CHSH-myc and 5'myc-SH structures. H locus targets included S alpha fused to Smu, Smu fused to S gamma 2b, and a germline S alpha region. The nature of two H locus targets suggests that the target need not be highly active transcriptionally. Switch recombination machinery is implicated in the translocation by the SH targets and by homology of certain c-myc breakpoints with normal switch recombination sites. Fusion regions revealed deletions, extraneous nucleotides, and one duplication. These results prompt a translocation model in which staggered single-stranded breaks on each chromosome are followed by single-strand excision or polymerization prior to ligation to the other chromosome.
Publisher: American Chemical Society (ACS)
Date: 10-06-1980
DOI: 10.1021/BI00553A026
Abstract: Familial hemiplegic migraine (FHM) is a rare, monogenic, autosomal dominant subtype of migraine, in which three genes,
Publisher: American Chemical Society (ACS)
Date: 10-06-1980
DOI: 10.1021/BI00553A027
Abstract: Several
Publisher: Wiley
Date: 24-03-2018
DOI: 10.1111/FEBS.14426
Publisher: Elsevier BV
Date: 05-1984
DOI: 10.1016/0092-8674(84)90306-4
Abstract: The myc oncogene is implicated here in T lymphocyte neoplasia. Cloning revealed a retroviral insert 0.7-1.3 kb 5' to c-myc in two T lymphomas induced by Soule murine leukemia virus and in a spontaneous T lymphoma ( Tikaut ) of an AKR mouse, a strain in which leukemogenesis involves recombinant retroviruses (MCF viruses). The tumor c-myc mRNAs appear normal but their level is approximately 5-fold higher than in most T lymphomas lacking c-myc rearrangement. Since each insert would be transcribed away from c-myc, its activation cannot involve the promoter of the long terminal repeat (LTR) but could reflect an enhancer, like that demonstrated within the Soule LTR. The Tikaut provirus has an MCF-like recombinant env gene and LTR sequence. MCF-like inserts were found near c-myc in seven of 31 other AKR T lymphomas two lie 3' to c-myc and the five upstream are oriented away from c-myc. We conclude that a quarter of retrovirus-induced T lymphomas involve activation of c-myc, probably via the LTR enhancer.
Publisher: Proceedings of the National Academy of Sciences
Date: 08-1980
Abstract: We have cloned an active gene for an immunoglobulin mu heavy (H) chain, bearing the variable (VH), joining (JH), and constant (C mu) sequences expressed in the IgM-secreting mouse plasmacytoma HPC-76. The mu gene was formed by somatic recombination between a VH gene and one of several JH genes, which are located about 7.7 kilobase pairs from the C mu gene in embryo DNA. The JH-C mu intervening sequence has suffered a deletion of about 2.7 kilobase pairs in HPC-76. Because the delection encompasses sequences required to switch an expressed VH-JH gene from C mu to another CH gene, it may represent a mechanism for "freezing" a lymphocyte clone at the stage of IgM expression. For the second (inactive) C mu allele in HPC-76, the entire joining and switch regions have been deleted functional inactivation of one allele may thus represent one mechanism by which a lymphocyte clone restricts expression to a single allele (allelic exclusion). Probes generated from the cloned mu gene allowed examination of the JH locus in B, Abelson "pre-B," and T lymphoma cell lines and a myeloid line, all of which cotain RNA species bearing C mu sequences. The B and pre-B lines exhibited recombination within both alleles of the JH locus, suggesting that both alleles may be expressed in some cells. The absence of the JH gene 5' to the recombination sites favors a deletion mechanism for VH-JH joining. Recombination within the JH locus was also detected in two out of four T lymphoma lines, but not in the myeloid line. This indicates that the mechanism by which B cells generate immunoglobulin ersity is operational in some T cells. Lines that synthesize mu RNA without JH rearrangement may have activated the C mu gene directly or have undergone recombination at a more distant locus.
Publisher: American Society of Hematology
Date: 21-03-2013
DOI: 10.1182/BLOOD-2013-01-475855
Abstract: ABT-199, a new Bcl-2–specific BH3 mimetic, is efficacious in vivo against mouse lymphomas without provoking thrombocytopenia. Treating mouse lymphomas with BH3 mimetic ABT-737 combined with bortezomib or purvalanol achieved long-term remission.
Publisher: Springer Science and Business Media LLC
Date: 04-11-2016
DOI: 10.1038/CDD.2016.125
Publisher: Elsevier BV
Date: 21-10-1994
DOI: 10.1016/0092-8674(94)90201-1
Abstract: The roles of p53 as an inducer and Bcl-2 as an inhibitor of apoptotic death were explored in lymphoid cells. Lymphocytes from p53-/- mice were radioresistant, but unexpectedly, cycling T lymphoma cells and mitogenically activated T lymphocytes from these animals underwent apoptosis after irradiation or genotoxic drug treatment. Hence, p53 is not the only mediator of apoptosis provoked by DNA damage. Irradiated p53-/- lymphoblasts expressing Bcl-2 were subject to growth arrest but resisted apoptosis. Their accumulation in G1 as well as G2 is suggestive of a p53-independent DNA-damage G1 checkpoint. Since Bcl-2 increased the clonogenic survival of the irradiated cells, expression of survival genes may pose a greater impediment to genotoxic cancer therapy than loss of p53.
Publisher: The Company of Biologists
Date: 03-2012
DOI: 10.1242/JCS.090514
Publisher: Springer Science and Business Media LLC
Date: 1994
DOI: 10.1038/367317A0
Publisher: Springer Science and Business Media LLC
Date: 12-1968
DOI: 10.1038/2201039A0
Abstract: No study has compared the associations of headache, anxiety, and depression at baseline with muscle soreness or pain (MS/P) at baseline and at the two-year follow-up point among outpatients with major depressive disorder (MDD). This study aimed to investigate the above issue. This study enrolled 155 outpatients with MDD at baseline, and 131 attended a two-year follow-up appointment. At baseline, migraine was diagnosed based on the International Classification of Headache Disorders, 2(nd) edition. MDD and anxiety disorders were diagnosed using the Structured Clinical Interview for DSM-IV-TR. The visual analog scale was used to evaluate the intensities of headache and MS/P in the neck, shoulder, back, upper limbs, and lower limbs. Depression and anxiety were evaluated using the Hospital Anxiety and Depression Scale. Multiple linear regressions were used to compare the associations of these factors with MS/P. Compared with anxiety disorders, migraine was more strongly associated with MS/P in all areas at baseline and in the upper and lower limbs at follow-up. Headache intensity at baseline was the factor most strongly associated with MS/P in all areas at baseline and follow-up after controlling for depression and anxiety. Headache intensity at baseline predicted MS/P at baseline and follow-up. Migraine and headache intensity are important factors related to MS/P at baseline and follow-up among patients with MDD. Integrating depression and headache treatment might be indicated to improve MS/P.
Publisher: The Company of Biologists
Date: 05-2022
DOI: 10.1242/DMM.049609
Abstract: Prompted by the occasion of International Women's Day, Joan Heath and DMM reunited Professors Suzanne Cory and Joan Steitz via Zoom to discuss their extraordinary careers and joint experiences in science. They also delve into past and present challenges for women in science, and discuss the role of scientists in a post-pandemic world.
Publisher: Springer Science and Business Media LLC
Date: 06-1999
Abstract: Certain Bcl-2 family members promote cell survival, whereas others promote apoptosis. To explore further how heterodimerization of opposing members affects survival activity, we have compared the abilities of the anti-apoptotic Bcl-w and A1 to bind to the pro-apoptotic Bax, Bak, Bad and Bik and to protect cells from their cytotoxic action. Bcl-w co-immunoprecipitated from cell lysates with Bax, Bak, Bad and Bik, but A1 bound only Bak and Bik. Mutation of A1 at a highly conserved glycine within the BH1 domain prevented binding, but the comparable Bcl-w mutant still bound Bak, Bad and Bik, indicating that the glycine is not essential for all heterodimerization. Bcl-w and A1 protected against apoptosis induced by over-expression of Bax or Bad but not that induced by Bak or Bik. With several gene pairs, binding and protection were discordant. The results may reflect critical threshold affinities but also suggest that certain pro-apoptotic proteins may also contribute to apoptosis by a mechanism independent of binding pro-survival proteins.
Publisher: Springer Science and Business Media LLC
Date: 03-11-2017
DOI: 10.1038/CDD.2017.161
Publisher: Elsevier BV
Date: 10-1977
DOI: 10.1016/0005-2787(77)90096-X
Abstract: It is shown that the DNA-dependent RNA polymerase of Escherichia coli can synthesize complementary RNA (cRNA) directly on rRNA and mRNA templates. Synthesis occurred preferentially in the presence of Mn2+ and at relatively high substrate and enzyme concentrations. No primer was required, and addition of oligo-U to a mRNA-dependent reaction gave no marked stimulation. Sedimentation analysis of cRNA made on different templates indicated that the products were mainly 2-4 S, but a fraction of the product was larger. Fingerprints of 32P-labelled cRNA made on 5 S rRNA and 18 S rRNA indicated that the complexity of the cRNAs was related to the size of the template, suggesting that a substantial portion of the templates were copied. This reaction provides a simple method for preparing cRNA of high specific activity for use in hybridisation studies, and possibly in sequence analysis. 32P-labelled cRNA made on 18 S and 28 S rRNA was a sensitive hybridisation probe for detection of the specific fragments of mouse DNA containing the rRNA genes.
Publisher: Elsevier BV
Date: 1985
DOI: 10.1016/0092-8674(85)90310-1
Abstract: A novel mechanism of oncogene activation by transposition of a tissue-specific cellular enhancer is described. A rearranged c-myc oncogene was cloned from murine plasmacytoma ABPC17 in the expectation that it would reflect the t(6 ) chromosome translocation carried by this tumor. The rearrangement instead reflects an insertion 361 bp 5' to the c-myc gene on chromosome 15. The insert conveys a 2.3 kb segment of the immunoglobulin heavy (H) chain locus from chromosome 12. Since the insertion introduces the lymphoid-specific enhancer from the JH-Smu region and also disrupts a region implicated in normal c-myc control, it may account for the c-myc transcription observed in ABPC17. The structure of the transposed segment and a corresponding deletion in the JH-Smu region suggests that the transposition reflects a complex recombination between chromosomes 15 and 12. Since the t(6 ) breakpoint is not near c-myc, chromosome 15 must have undergone an independent exchange with chromosome 6.
Publisher: Springer Science and Business Media LLC
Date: 03-1994
DOI: 10.1038/368457A0
Abstract: Expression of antigen receptors is vital for the development of B and T lymphocytes. In mice with the scid mutation, which are unable to make productive rearrangements of their immunoglobulin and T-cell receptor (TCR) genes, lymphopoiesis aborts at an early stage. The death of the immature lymphocytes by apoptosis is postulated to result from a failure to receive a survival signal induced by receptor engagement. Consistent with this hypothesis, introduction of immunoglobulin or TCR transgenes into scid mice promoted an increase in B- or T-lymphoid cells, respectively. As the protein encoded by the bcl-2 gene can inhibit cell death, we tested whether lymphopoiesis could be rescued in scid mice by crossing in a bcl-2 transgene. Strikingly, the bcl-2/scid mice accumulated almost normal numbers of B-lymphoid cells which lacked surface immunoglobulin but expressed markers of maturity. T-cell development remained blocked. Introducing a TCR transgene enabled bcl-2/scid mice to develop normal numbers of CD4+8+ thymocytes even in the absence of immunological selection, suggesting that T cells become competent to respond to bcl-2 protein only after the TCR complex is displayed at the cell surface.
Publisher: Elsevier BV
Date: 08-2016
DOI: 10.1016/J.TRECAN.2016.07.001
Abstract: Mutations that impair apoptosis contribute to cancer development and reduce the effectiveness of conventional anti-cancer therapies. These insights and understanding of how the B cell lymphoma (BCL)-2 protein family governs apoptosis have galvanized the search for a new class of cancer drugs that target its pro-survival members by mimicking their natural antagonists, the BCL-2 homology (BH)3-only proteins. Successful initial clinical trials of the BH3 mimetic venetoclax/ABT-199, specific for BCL-2, have led to its recent licensing for refractory chronic lymphocytic leukemia and to multiple ongoing trials for other malignancies. Moreover, preclinical studies herald the potential of emerging BH3 mimetics targeting other BCL-2 pro-survival members, particularly myeloid cell leukemia (MCL)-1, for multiple cancer types. Thus, BH3 mimetics seem destined to become powerful new weapons in the arsenal against cancer. This review sketches the discovery of the BCL-2 family and its impact on cancer development and therapy describes how interactions of family members trigger apoptosis outlines the development of BH3 mimetic drugs and discusses their potential to advance cancer therapy.
Publisher: Informa UK Limited
Date: 25-09-2020
Publisher: Springer Science and Business Media LLC
Date: 09-04-2015
Publisher: Springer Science and Business Media LLC
Date: 23-11-2019
Publisher: Wiley
Date: 10-1981
DOI: 10.1111/J.1600-065X.1981.TB00454.X
Abstract: Following the explosive growth in chemical and biological data, the shift from traditional methods of drug discovery to computer-aided means has made data mining and machine learning methods integral parts of today's drug discovery process. In this paper, extreme gradient boosting (Xgboost), which is an ensemble of Classification and Regression Tree (CART) and a variant of the Gradient Boosting Machine, was investigated for the prediction of biological activity based on quantitative description of the compound's molecular structure. Seven datasets, well known in the literature were used in this paper and experimental results show that Xgboost can outperform machine learning algorithms like Random Forest (RF), Support Vector Machines (LSVM), Radial Basis Function Neural Network (RBFN) and Naïve Bayes (NB) for the prediction of biological activities. In addition to its ability to detect minority activity classes in highly imbalanced datasets, it showed remarkable performance on both high and low ersity datasets.
Publisher: Informa UK Limited
Date: 04-1992
Abstract: Irradiated mice reconstituted with bone marrow cells infected with a retrovirus carrying the bcr-abl oncogene of human chronic myeloid leukemia are subject to a range of neoplastic hematopoietic diseases, both myeloid and lymphoid. Comparison of DBA/2 and C57BL/6 mice has revealed a marked strain difference in susceptibility to the various tumor types. The present study, performed with BALB/c mice, indicates that the kinetics and nature of the induced disease can be modulated by the infection procedure, as well as the genetic background, and that retroviral regulatory sequences may influence the outcome. A distinctive clonal myeloproliferative disorder, somewhat akin to chronic myeloid leukemia but with prominent erythroid and mast cell components, as well as granulocytic excess, was characterized.
Publisher: American Chemical Society (ACS)
Date: 04-1981
DOI: 10.1021/BI00512A047
Abstract: Immunoglobulin heavy-chain expression is initiated by recombination between a variable region (VH) gene and one of several joining region (JH) genes located near the mu constant region (Cmu) gene, and the active VH gene can subsequently switch to another CH gene. That the general mechanism for CH switching involves recombination between sites within the JH-Cmu intervening sequence and the 5' flanking region of another CH gene is supported here by Southern blot hybridization analysis of eight IgG- and IgA-secreting plasmacytomas. An alternative model requiring successive VH linkage to similar JH clusters near each CH gene is shown to be very unlikely since the mouse genome appears to contain only one complement of the JH locus and no JH gene was detectable within large cloned sequences flanking germline C gamma 3 and C gamma 1 genes. Thus, VH-JH joining and CH switching are mediated by separate regions of "the joining-switch" or J-S element. In each plasmacytoma examined, the J-S element had undergone recombination within both the JH locus and the switch region and was shown to be linked to the functional CH gene in an IgG3, and IgG1, and three IgA secretors. Both JH joining and CH switching occurred by deletion of DNA. Switch recombination occurred at more than one site within the J-S element in different lines, even for recombination with the same CH gene. Significantly, although heavy-chain expression is restricted to one allele ("allelic exclusion"), all rearranged in each plasmacytoma. Some rearrangements were aberrant, involving, for ex le, deletion of all JH genes from the allele. Hence, an error-prone recombination machinery may account for allelic exclusion in many plasmacytomas.
Publisher: Wiley
Date: 03-1969
DOI: 10.1111/J.1432-1033.1969.TB00500.X
Abstract: Echogenicity is an ultrasound measure that reflects arterial wall composition. In adult populations, lower carotid intima-media echogenicity relates to an unfavorable cardiovascular risk burden yet appears to reflect a different aspect of arterial wall remodeling than carotid intima-media thickness (CIMT). Since studies on carotid intima-media echogenicity earlier in life are lacking, we investigated associations between adolescent cardiovascular risk factors and young adulthood carotid intima-media echogenicity and compared this to CIMT. In 736 participants of the Atherosclerosis Risk in Young Adults study, information on adolescent anthropometrics, puberty stage, and systolic blood pressure (SBP) was available. In young adulthood, demographics, anthropometrics, and fasting plasma s les were collected. Common CIMT and echogenicity, quantified as gray-scale median (GSM), were evaluated using B-mode ultrasonography. Lower and higher GSM values, respectively, represented lower and higher echogenicity. Associations of adolescent body mass index and SBP with young adulthood GSM and CIMT were evaluated using linear regression analysis. Mean age was 13.5 years in adolescence and 28.4 years in young adulthood (difference: 14.9 years). After full adjustment, adolescent body mass index related to GSM (β=-1.62/SD 95% CI: -2.79, -0.46 P=0.006), independent of CIMT. Adolescent SBP did not relate to GSM. Moreover, adolescent body mass index (β=8.06 μm/SD [95% CI: 4.12, 11.99], P<0.001) and SBP (β=4.69 μm/SD [95% CI: 0.84, 8.54], P=0.02) related to CIMT. Adolescent body mass index related to GSM and CIMT in young adulthood SBP only related to CIMT. Hence, carotid intima-media echogenicity appears to be involved in arterial wall remodeling, yet may mimic a different facet of this process than CIMT.
Publisher: Proceedings of the National Academy of Sciences
Date: 12-04-2004
Abstract: Impaired apoptosis is now recognized to be central to tumor development. Bcl2, activated by chromosomal translocation in human follicular lymphoma, promotes oncogenesis by inhibiting apoptosis. Bim, a distant proapoptotic relative, is emerging as a major physiologic antagonist of Bcl2. Here, we show that loss of Bim is oncogenic. Bim protein levels were elevated in the apoptosis-prone B lymphoid cells of Eμ- Myc -transgenic mice, and Bim -mutant Eμ- Myc mice had increased numbers of IgM-bearing B cells. Eμ- Myc -expressing B lymphoid cells deficient in Bim were refractory to apoptosis induced in vitro by cytokine deprivation or antigen receptor cross-linking. Thus, Bim is induced by Myc in B cells and mediates apoptosis. Remarkably, inactivation of even a single allele of Bim accelerated Myc-induced development of tumors, particularly acute B cell leukemia. None of the primary tumors from Bim +/- Eμ- Myc mice displayed loss of the second allele of Bim . These findings indicate that Bim is a tumor suppressor, at least in B lymphocytes, and is haploinsufficient. Whereas the p19Arf 53 pathway is frequently mutated in tumors arising in Bim + / + Eμ- Myc mice, it was unaffected in most Bim-deficient tumors, indicating that Bim reduction is an effective alternative to loss of p53 function.
Publisher: Springer Science and Business Media LLC
Date: 12-1985
DOI: 10.1038/318533A0
Abstract: Transgenic mice bearing the cellular myc oncogene coupled to the immunoglobulin mu or kappa enhancer frequently develop a fatal lymphoma within a few months of birth. Since the tumours represent represent both immature and mature B lymphocytes, constitutive c-myc expression appears to be highly leukaemogenic at several stages of B-cell maturation. These myc mice should aid study of lymphoma development, B-cell ontogeny and immunoglobulin regulation.
Publisher: American Society of Hematology
Date: 14-06-2012
DOI: 10.1182/BLOOD-2011-12-400929
Abstract: The BH3-mimetic ABT-737 and an orally bioavailable compound of the same class, navitoclax (ABT-263), have shown promising antitumor efficacy in preclinical and early clinical studies. Although both drugs avidly bind Bcl-2, Bcl-xL, and Bcl-w in vitro, we find that Bcl-2 is the critical target in vivo, suggesting that patients with tumors overexpressing Bcl-2 will probably benefit. In human non-Hodgkin lymphomas, high expression of Bcl-2 but not Bcl-xL predicted sensitivity to ABT-263. Moreover, we show that increasing Bcl-2 sensitized normal and transformed lymphoid cells to ABT-737 by elevating proapoptotic Bim. In striking contrast, increasing Bcl-xL or Bcl-w conferred robust resistance to ABT-737, despite also increasing Bim. Cell-based protein redistribution assays unexpectedly revealed that ABT-737 disrupts Bcl-2/Bim complexes more readily than Bcl-xL/Bim or Bcl-w/Bim complexes. These results have profound implications for how BH3-mimetics induce apoptosis and how the use of these compounds can be optimized for treating lymphoid malignancies.
Publisher: Elsevier BV
Date: 04-1998
Publisher: Elsevier BV
Date: 12-1975
DOI: 10.1016/S0022-2836(75)80170-7
Abstract: To make clear the role of the C terminus of a surface protein antigen (PAc) of Streptococcus mutans, stepwise truncations beginning at the C terminus of PAc were performed by utilizing site-directed mutagenesis. A remarkable increase in the amount of cell-free PAc was observed upon deletion of four or more amino acid residues at the C terminus. On the other hand, the amount of cell surface PAc gradually decreased when increasing numbers (four or more) of amino acid residues were deleted at the C terminus, and deletion of six amino acids involving both the total charged tail and Leu, an amino acid residue immediately upstream of the charged tail, resulted in a drastic reduction in the amount of cell surface PAc. These results indicate that the cytoplasmic charged tail and Leu residue are required for cell surface localization of PAc in S. mutans.
Publisher: American Society of Hematology
Date: 15-03-2004
DOI: 10.1182/BLOOD-2003-07-2469
Abstract: In human follicular lymphoma the t(14 18) chromosome translocation activates the antiapoptotic oncogene Bcl2 by linking it to the immunoglobulin heavy chain (IGH) locus. Transgenic mice expressing Bcl2 controlled by an Igh enhancer (Eμ) do not develop follicular lymphoma, although they do have an increased incidence of other B-lymphoid neoplasms. We have now analyzed tumorigenesis in mice bearing a Bcl2 transgene controlled by Vav gene regulatory sequences (VavP), which confer expression in multiple hematopoietic lineages. Unlike Eμ-Bcl2 mice, many VavP-Bcl2 mice older than 10 months developed follicular lymphoma. Young VavP-Bcl2 mice had an overabundance of enlarged germinal centers and greatly elevated numbers of cycling B cells that had undergone IgH class switching and V-gene hypermutation. The peripheral T-cell compartment was larger in the VavP-Bcl2 mice than in Eμ-Bcl2 strains and, notably, CD4 T cells were 5-fold increased over normal. The germinal center hyperplasia required CD4 T cells, because it could be abolished by anti-CD4 antibody in vivo. VavP-Bcl2 mice also had a propensity to develop kidney disease of the autoimmune type. We suggest that the increased survival capacity of B and T cells fosters prolonged germinal center reactions, and that autoreactivity and hypermutation conspire to generate follicular lymphoma.
Publisher: Proceedings of the National Academy of Sciences
Date: 18-11-2008
Abstract: Deregulated Myc expression drives many human cancers, including Burkitt's lymphoma and a highly aggressive subset of diffuse large cell lymphomas. Myc-driven tumors often display resistance to chemotherapeutics because of acquisition of mutations that impair the apoptosis pathway regulated by the Bcl-2 protein family. Given the need to identify new therapies for such lymphomas, we have evaluated the efficacy of ABT-737, a small molecule that mimics the action of the BH3-only proteins, natural antagonists of the prosurvival Bcl-2 proteins. ABT-737 selectively targets certain prosurvival proteins (Bcl-2, Bcl-x L , and Bcl-w) but not others (Mcl-1 and A1). We treated mice transplanted with lymphomas derived either from Eμ- myc transgenic mice or Eμ- myc mice that also expressed an Eμ- bcl -2 transgene. As a single agent, ABT-737 significantly prolonged the survival of mice transplanted with the myc / bcl -2 lymphomas but was ineffective for the myc lymphomas, probably because of the relatively higher Mcl-1 levels found in the latter. Strikingly, when combined with low-dose cyclophosphamide, ABT-737 produced sustained disease-free survival of all animals transplanted with two of three myc / bcl -2 lymphomas tested. The combination therapy was also more effective against some myc lymphomas than treatment with either agent alone. Our data suggest that antagonism of Bcl-2 with small organic compounds is an attractive approach to enhance the efficacy of conventional therapy for the treatment of Myc-driven lymphomas that over-express this prosurvival molecule.
Publisher: American Society of Hematology
Date: 24-01-2020
Abstract: Deregulated over-expression of MYC is implicated in the development and malignant progression of most (~70%) human tumors. MYC drives cell growth and proliferation but also, at high levels, promotes apoptosis. Here, we report that the proliferative capacity of MYC-driven normal and neoplastic B lymphoid cells depends on MNT, a MYC-related transcriptional repressor. Our genetic data establish that MNT synergises with MYC by suppressing MYC-driven apoptosis and that it does so primarily by reducing the level of pro-apoptotic BIM. In Em-Myc mice, which model the MYC/IGH chromosome translocation in Burkitt's lymphoma, homozygous Mnt deletion greatly reduced lymphoma incidence by enhancing apoptosis and markedly decreasing premalignant B lymphoid cell populations. Strikingly, by inducing Mnt deletion within transplanted fully-malignant Em-Myc lymphoma cells, we significantly extended transplant recipient survival. The dependency of lymphomas on MNT for survival suggests that drugs inhibiting MNT could significantly boost therapy of MYC-driven tumors by enhancing intrinsic MYC-driven apoptosis.
Publisher: Elsevier BV
Date: 04-1991
Publisher: Springer Science and Business Media LLC
Date: 04-1968
DOI: 10.1038/218232A0
Abstract: The immune system plays an important role in regulating tumor growth and metastasis. Classical monocytes promote tumorigenesis and cancer metastasis, but how nonclassical "patrolling" monocytes (PMo) interact with tumors is unknown. Here we show that PMo are enriched in the microvasculature of the lung and reduce tumor metastasis to lung in multiple mouse metastatic tumor models. Nr4a1-deficient mice, which specifically lack PMo, showed increased lung metastasis in vivo. Transfer of Nr4a1-proficient PMo into Nr4a1-deficient mice prevented tumor invasion in the lung. PMo established early interactions with metastasizing tumor cells, scavenged tumor material from the lung vasculature, and promoted natural killer cell recruitment and activation. Thus, PMo contribute to cancer immunosurveillance and may be targets for cancer immunotherapy.
Publisher: Springer Science and Business Media LLC
Date: 10-1979
DOI: 10.1038/281394A0
Publisher: American Society of Hematology
Date: 15-07-2006
DOI: 10.1182/BLOOD-2006-01-0172
Abstract: Deregulated MYC expression has been implicated in the etiology of many human cancers, including hematopoietic malignancies. To explore the impact of widespread constitutive MYC expression in the hematopoietic compartment, we have used a vector containing regulatory elements of the Vav gene to generate transgenic mice. VavP-MYC mice are highly tumor-prone and the level of MYC was found to influence both the kinetics and nature of the malignancies that developed. Whereas aggressive T-cell lymphomas rapidly overwhelmed the highest-expressing line, late-onset monocytic tumors greatly predominated in 2 low-expressing lines. These monocytic tumors most likely arise from abnormal macrophage colony-stimulating factor (M-CSF)–dependent progenitor cells having enhanced self-generative capacity. There appears to be a sharp threshold for MYC-induced T-cell lymphomagenesis because merely doubling the MYC level in a low-expressing line by breeding homozygous transgenic animals switched the phenotype from primarily monocytic tumors to exclusively T-cell tumors. Even the low level of MYC, however, clearly affected T-cell cycling, size, and sensitivity to apoptosis, and coexpression of a BCL2 transgene promoted efficient T-cell lymphomagenesis. The implication is that MYC level affects the spontaneous acquisition of synergistic oncogenic mutations.
Publisher: Springer Science and Business Media LLC
Date: 10-1999
DOI: 10.1038/44035
Publisher: Springer Science and Business Media LLC
Date: 11-1990
DOI: 10.1038/348331A0
Abstract: The putative oncogene bcl-2 is juxtaposed to the immunoglobulin heavy chain (Igh) locus by the t(14 ) chromosomal translocation typical of human follicular B-cell lymphomas. The bcl-2 gene product is not altered by the translocation, but its expression is deregulated, presumably by the Igh enhancer E mu. Constitutive bcl-2 expression seems to augment cell survival, as infection with a bcl-2 retrovirus enables certain growth factor-dependent mouse cell lines to maintain viability when deprived of factor. Furthermore, high levels of the bcl-2 product can protect human B and T lymphoblasts under stress and thereby confer a growth advantage. Mice expressing a bcl-2 transgene controlled by the Igh enhancer accumulate small non-cycling B cells which survive unusually well in vitro but do not show a propensity for spontaneous tumorigenesis. In contrast, an analogous myc transgene, designed to mimic the myc-Igh translocation product typical of Burkitt's lymphoma and rodent plasmacytoma, promotes B lymphoid cell proliferation and predisposes mice to malignancy in pre-B and B lymphoid cells. Previous experiments have suggested that bcl-2 can cooperate with deregulated myc to improve in vitro growth of pre-B and B cells. Here we describe a marked synergy between bcl-2 and myc in doubly transgenic mice. E mu-bcl-2/myc mice show hyperproliferation of pre-B and B cells and develop tumours much faster than E mu-myc mice. Suprisingly, the tumours derive from a cell with the hallmarks of a primitive haemopoietic cell, perhaps a lymphoid-committed stem cell.
Publisher: Elsevier BV
Date: 12-2002
DOI: 10.1016/S0955-0674(02)00381-2
Abstract: Activation of the caspases that initiate apoptosis typically requires cognate scaffold proteins, including CED-4 in Caenorhabditis elegans, Apaf-1 in mammals and Dark in Drosophila. Each scaffold protein oligomerizes procaspases into a complex called the apoptosome, but the regulation and biological roles of the scaffolds differ. Whereas CED-4 is restrained by the Bcl-2 homologue CED-9, Apaf-1 is inhibited by its WD40 repeat region, until it is activated by cytochrome c, derived from damaged mitochondria. Although Dark also has a WD40 region, its activation does not seem to involve cytochrome c. CED-4 is essential for apoptosis in the worm and Dark for many apoptotic responses in the fly, but the Apaf-1/caspase-9 system probably lifies rather than initiates the mammalian caspase cascade.
Publisher: Proceedings of the National Academy of Sciences
Date: 13-10-1998
Publisher: Springer Science and Business Media LLC
Date: 09-1988
DOI: 10.1038/335440A0
Abstract: A common feature of follicular lymphoma, the most prevalent haematological malignancy in humans, is a chromosome translocation (t(14 ] that has coupled the immunoglobulin heavy chain locus to a chromosome 18 gene denoted bcl-2. By analogy with the translocated c-myc oncogene in other B-lymphoid tumours bcl-2 is a candidate oncogene, but no biological effects of bcl-2 have yet been reported. To test whether bcl-2 influences the growth of haematopoietic cells, either alone or together with a deregulated c-myc gene, we have introduced a human bcl-2 complementary DNA using a retroviral vector into bone marrow cells from either normal or E mu-myc transgenic mice, in which B-lineage cells constitutively express the c-myc gene. Bcl-2 cooperated with c-myc to promote proliferation of B-cell precursors, some of which became tumorigenic. To determine how bcl-2 expression impinges on growth factor requirements, the gene was introduced into a lymphoid and a myeloid cell line that require interleukin 3 (IL-3). In the absence of IL-3, bcl-2 promoted the survival of the infected cells but they persisted in a G0 state, rather than proliferating. These results argue that bcl-2 provided a distinct survival signal to the cell and may contribute to neoplasia by allowing a clone to persist until other oncogenes, such as c-myc, become activated.
Publisher: Proceedings of the National Academy of Sciences
Date: 20-06-2017
Abstract: Prokaryotic and eukaryotic organisms use analogous pathways to synthesize protein cofactors called iron–sulfur clusters. An unexplained difference between pathways is the functional requirements of the respective cysteine desulfurases. In eukaryotes, the cysteine desulfurase NFS1 requires additional accessory subunits for function. The lack of structural information has limited mechanistic insight into the role of these accessory proteins in mitochondrial Fe–S cluster biosynthesis. Here we determined crystallographic and electron microscopic structures of the NFS1–ISD11–ACP subcomplex. These results reveal an unexpected cysteine desulfurase architecture that reconciles mechanistic differences between the prokaryotic and eukaryotic systems, reveals the basis of control of iron–sulfur cluster assembly through fatty acid synthesis, and serves as a structural foundation for investigating human diseases related to iron–sulfur cluster assembly.
Publisher: Elsevier BV
Date: 06-1977
Publisher: Elsevier BV
Date: 09-1994
DOI: 10.1016/1074-7613(94)90094-9
Abstract: B-lymphoid and myeloid development are markedly perturbed in a unique transgenic mouse strain, max 41. Pro-B, pre-B, and B lymphocytes were severely reduced but granulocytes were greatly elevated. This phenotype could be adoptively transferred with bone marrow cells. It was not alleviated by bcl-2 or myc transgenes that promote lymphocyte survival or proliferation. Bitransgenic myc/max 41 mice developed pre-B cell lymphoma. An accompanying massive granulocytosis unexpectedly proved to be clonally derived from the pre-B lymphoma cells. These observations suggest that B lymphopoiesis in max 41 mice has been erted to granulocyte production. Since neither cell type expressed the transgene, this novel lymphomyeloid deviation probably reflects insertional alteration of a hematopoietic regulatory gene.
Publisher: Springer Science and Business Media LLC
Date: 21-02-2002
DOI: 10.1038/415922A
Location: United Kingdom of Great Britain and Northern Ireland
Location: Australia
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Funder: Worldwide Cancer Research
View Funded ActivityStart Date: 1997
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Funder: National Health and Medical Research Council
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Funder: National Health and Medical Research Council
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Funder: National Health and Medical Research Council
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Funder: National Health and Medical Research Council
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Funder: National Health and Medical Research Council
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