ORCID Profile
0000-0002-3853-2614
Current Organisation
Hudson Institute of Medical Research
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Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Cell Development, Proliferation and Death | Developmental Genetics (incl. Sex Determination) | Gene Expression (incl. Microarray and other genome-wide approaches) | Genetics | Proteomics and Intermolecular Interactions (excl. Medical Proteomics) | Animal Developmental and Reproductive Biology | Medical Biochemistry and Metabolomics | Biochemistry and Cell Biology | Central Nervous System | Regenerative Medicine (incl. Stem Cells and Tissue Engineering) | Medical Biochemistry and Metabolomics not elsewhere classified | Nanobiotechnology |
ANZSRC Socio-Economic Objective (SEO)
Expanding Knowledge in the Biological Sciences | Animal Production and Animal Primary Products not elsewhere classified | Reproductive System and Disorders | Cardiovascular System and Diseases | Nervous System and Disorders | Blood Disorders | Men's Health
Related Links
Publications
GILZ-dependent modulation of mTORC1 regulates spermatogonial maintenance
Publisher: The Company of Biologists
Date: 2018
DOI: 10.1242/DEV.165324
Abstract: Male fertility is dependent on spermatogonial stem cells (SSCs) that self-renew and produce differentiating germ cells. Growth factors produced within the testis are essential for SSC maintenance but intrinsic factors dictating SSC response to these stimuli poorly characterised. Here we studied the role of GILZ, a TSC22D family protein and spermatogenesis regulator, in spermatogonial function and signalling. While broadly expressed in the germline, GILZ was prominent in undifferentiated spermatogonia and Gilz deletion in adults resulted in exhaustion of the GFRα1+ SSC-containing population and germline degeneration. GILZ loss was associated with mTORC1 activation, suggesting enhanced growth factor signalling. Expression of deubiquitinase USP9X, an mTORC1 modulator required for spermatogenesis, was disrupted in Gilz mutants. Treatment with an mTOR inhibitor rescued GFRα1+ spermatogonial failure, indicating that GILZ-dependent mTORC1 inhibition is critical for SSC maintenance. Analysis of cultured undifferentiated spermatogonia lacking GILZ confirmed aberrant activation of ERK MAPK upstream mTORC1 plus USP9X downregulation and interaction of GILZ with TSC22D proteins. Our data indicate an essential role for GILZ-TSC22D complexes in ensuring appropriate response of undifferentiated spermatogonia to growth factors via distinct inputs to mTORC1.
Germline Stem Cell Activity Is Sustained by SALL4-Dependent Silencing of Distinct Tumor Suppressor Genes
Publisher: Elsevier BV
Date: 09-2017
CIP2A Promotes Proliferation of Spermatogonial Progenitor Cells and Spermatogenesis in Mice
Publisher: Public Library of Science (PLoS)
Date: 26-03-2012
Development of promyelocytic zinc finger and ThPOK-expressing innate γδ T cells is controlled by strength of TCR signaling and Id3
Publisher: The American Association of Immunologists
Date: 28-12-2010
Abstract: The broad-complex tramtrack and bric a brac-zinc finger transcriptional regulator(BTB-ZF), promyelocytic leukemia zinc finger (PLZF), was recently shown to control the development of the characteristic innate T cell phenotype and effector functions of NK T cells. Interestingly, the ectopic expression of PLZF was shown to push conventional T cells into an activated state that seems to be proinflammatory. The factors that control the normal expression of PLZF in lymphocytes are unknown. In this study, we show that PLZF expression is not restricted to NK T cells but is also expressed by a subset of γδ T cells, functionally defining distinct subsets of this innate T cell population. A second BTB-ZF gene, ThPOK, is important for the phenotype of the PLZF-expressing γδ T cells. Most importantly, TCR signal strength and expression of inhibitor of differentiation gene 3 control the frequency of PLZF-expressing γδ T cells. This study defines the factors that control the propensity of the immune system to produce potentially disease-causing T cell subsets.
Essential role of Plzf in maintenance of spermatogonial stem cells
Publisher: Springer Science and Business Media LLC
Date: 23-05-2004
DOI: 10.1038/NG1367
Generation of functional multipotent adult stem cells from GPR125+ germline progenitors
Publisher: Springer Science and Business Media LLC
Date: 09-2007
DOI: 10.1038/NATURE06129
Characterization, Cryopreservation, and Ablation of Spermatogonial Stem Cells in Adult Rhesus Macaques
Publisher: Oxford University Press (OUP)
Date: 09-2007
DOI: 10.1634/STEMCELLS.2007-0143
Abstract: Spermatogonial stem cells (SSCs) are at the foundation of mammalian spermatogenesis. Whereas rare Asingle spermatogonia comprise the rodent SSC pool, primate spermatogenesis arises from more abundant Adark and Apale spermatogonia, and the identity of the stem cell is subject to debate. The fundamental differences between these models highlight the need to investigate the biology of primate SSCs, which have greater relevance to human physiology. The alkylating chemotherapeutic agent, busulfan, ablates spermatogenesis in rodents and causes infertility in humans. We treated adult rhesus macaques with busulfan to gain insights about its effects on SSCs and spermatogenesis. Busulfan treatment caused acute declines in testis volume and sperm counts, indicating a disruption of spermatogenesis. One year following high-dose busulfan treatment, sperm counts remained undetectable, and testes were depleted of germ cells. Similar to rodents, rhesus spermatogonia expressed markers of germ cells (VASA, DAZL) and stem rogenitor spermatogonia (PLZF and GFRα1), and cells expressing these markers were depleted following high-dose busulfan treatment. Furthermore, fresh or cryopreserved germ cells from normal rhesus testes produced colonies of spermatogonia, which persisted as chains on the basement membrane of mouse seminiferous tubules in the primate to nude mouse xenotransplant assay. In contrast, testis cells from animals that received high-dose busulfan produced no colonies. These studies provide basic information about rhesus SSC activity and the impact of busulfan on the stem cell pool. In addition, the germ cell-depleted testis model will enable autologous/homologous transplantation to study stem cell/niche interactions in nonhuman primate testes. Disclosure of potential conflicts of interest is found at the end of this article.
Essential Role of the p110β Subunit of Phosphoinositide 3-OH Kinase in Male Fertility
Publisher: American Society for Cell Biology (ASCB)
Date: 03-2010
Abstract: Phosphoinositide 3-kinases (PI3K) are key molecular players in male fertility. However, the specific roles of different p110 PI3K catalytic subunits within the spermatogenic lineage have not been characterized so far. Herein, we report that male mice expressing a catalytically inactive p110β develop testicular hypotrophy and impaired spermatogenesis, leading to a phenotype of oligo-azoospermia and defective fertility. The examination of testes from p110β-defective tubules demonstrates a widespread loss in spermatogenic cells, due to defective proliferation and survival of pre- and postmeiotic cells. In particular, p110β is crucially needed in c-Kit–mediated spermatogonial expansion, as c-Kit–positive cells are lost in the adult testis and activation of Akt by SCF is blocked by a p110β inhibitor. These data establish that activation of the p110β PI3K isoform by c-Kit is required during spermatogenesis, thus opening the way to new treatments for c-Kit positive testicular cancers.
Erratum
Publisher: American Association for the Advancement of Science (AAAS)
Date: 25-05-2010
The BTB-zinc finger transcriptional regulator PLZF controls the development of invariant natural killer T cell effector functions
Publisher: Springer Science and Business Media LLC
Date: 27-07-2008
DOI: 10.1038/NI.1641
Mechanisms regulating mammalian spermatogenesis and fertility recovery following germ cell depletion
Publisher: Springer Science and Business Media LLC
Date: 28-06-2019
DOI: 10.1007/S00018-019-03201-6
Abstract: Mammalian spermatogenesis is a highly complex multi-step process sustained by a population of mitotic germ cells with self-renewal potential known as spermatogonial stem cells (SSCs). The maintenance and regulation of SSC function are strictly dependent on a supportive niche that is composed of multiple cell types. A detailed appreciation of the molecular mechanisms underpinning SSC activity and fate is of fundamental importance for spermatogenesis and male fertility. However, different models of SSC identity and spermatogonial hierarchy have been proposed and recent studies indicate that cell populations supporting steady-state germline maintenance and regeneration following damage are distinct. Importantly, dynamic changes in niche properties may underlie the fate plasticity of spermatogonia evident during testis regeneration. While formation of spermatogenic colonies in germ-cell-depleted testis upon transplantation is a standard assay for SSCs, differentiation-primed spermatogonial fractions have transplantation potential and this assay provides readout of regenerative rather than steady-state stem cell capacity. The characterisation of spermatogonial populations with regenerative capacity is essential for the development of clinical applications aimed at restoring fertility in in iduals following germline depletion by genotoxic treatments. This review will discuss regulatory mechanisms of SSCs in homeostatic and regenerative testis and the conservation of these mechanisms between rodent models and man.
Cep55 overexpression causes male-specific sterility in mice by suppressing Foxo1 nuclear retention through sustained activation of PI3K/Akt signaling.
Publisher: Wiley
Date: 17-04-2018
The transcription factor Pokemon: a new key player in cancer pathogenesis
Publisher: American Association for Cancer Research (AACR)
Date: 10-2005
DOI: 10.1158/0008-5472.CAN-05-1055
Abstract: Learning how critical cell regulatory pathways are controlled may lead to new opportunities for cancer treatment. We recently identified the transcription factor Pokemon as a central regulator of the important tumor suppressor ARF. Pokemon is overexpressed in multiple human cancers and cells lacking Pokemon are refractory to oncogenic transformation. These findings suggest that Pokemon may offer an effective new target for cancer therapeutics.
A novel signal transduction cascade involving direct physical interaction of the renin/prorenin receptor with the transcription factor promyelocytic zinc finger protein
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-12-2006
DOI: 10.1161/01.RES.0000251700.00994.0D
Abstract: A human renin rorenin receptor (RER) has recently been cloned. To gain insight into the molecular function of the RER, we studied its signal transduction mechanisms. Initially, we found a ubiquitous and intracellular expression pattern of the human RER. Consistently, we observed several transcriptional start sites and a high promoter activity of the human RER. We could identify the transcription factor promyelocytic zinc finger (PLZF) protein as a direct protein interaction partner of the C-terminal domain of the RER by yeast 2-hybrid screening and coimmunoprecipitation. Coimmunoprecipitation experiments also indicated homodimerization of the RER. On activation of the RER by renin, PLZF is translocated into the nucleus and represses transcription of the RER itself, thereby creating a very short negative feedback loop, but activates transcription of the p85α subunit of the phosphatidylinositol-3 kinase (PI3K-p85α). Small interfering RNA against the RER abolished these effects. A PLZF cis -element in the RER promoter was identified by site-directed mutagenesis and electrophoretic mobility-shift assay. Renin stimulation caused a 6-fold recruitment of PLZF to this promoter region as shown by chromatin immunoprecipitation. Moreover, renin stimulation of rat H9c2 cardiomyoblasts induced an increase of cell number and a decrease of apoptosis. These effects were partly abolished by PI3K inhibition and completely abrogated by small interfering RNA against PLZF. Finally, experiments in PLZF knockout mice confirmed the role of PLZF as an upstream regulator of RER and PI3K-p85α. Our data demonstrate the existence of a novel signal transduction pathway involving the ligand renin, RER, and the transcription factor PLZF, which is of physiological and putative pathophysiological relevance.
Disruption of PLZP in Mice Leads to Increased T-Lymphocyte Proliferation, Cytokine Production, and Altered Hematopoietic Stem Cell Homeostasis
Publisher: Informa UK Limited
Date: 12-2004
DDX5 plays essential transcriptional and post-transcriptional roles in the maintenance and function of spermatogonia.
Publisher: Springer Science and Business Media LLC
Date: 23-05-2019
DOI: 10.1038/S41467-019-09972-7
Abstract: Mammalian spermatogenesis is sustained by mitotic germ cells with self-renewal potential known as undifferentiated spermatogonia. Maintenance of undifferentiated spermatogonia and spermatogenesis is dependent on tightly co-ordinated transcriptional and post-transcriptional mechanisms. The RNA helicase DDX5 is expressed by spermatogonia but roles in spermatogenesis are unexplored. Using an inducible knockout mouse model, we characterise an essential role for DDX5 in spermatogonial maintenance and show that Ddx5 is indispensable for male fertility. We demonstrate that DDX5 regulates appropriate splicing of key genes necessary for spermatogenesis. Moreover, DDX5 regulates expression of cell cycle genes in undifferentiated spermatogonia post-transcriptionally and is required for cell proliferation and survival. DDX5 can also act as a transcriptional co-activator and we demonstrate that DDX5 interacts with PLZF, a transcription factor required for germline maintenance, to co-regulate select target genes. Combined, our data reveal a critical multifunctional role for DDX5 in regulating gene expression programmes and activity of undifferentiated spermatogonia.
A role for mitogen-activated protein kinase activation by integrins in the pathogenesis of psoriasis
Publisher: American Society for Clinical Investigation
Date: 15-08-2001
DOI: 10.1172/JCI12153
Repression of kit Expression by Plzf in Germ Cells
Publisher: Informa UK Limited
Date: 10-2007
DOI: 10.1128/MCB.00479-07
Expression of Activated MEK1 in Differentiating Epidermal Cells Is Sufficient to Generate Hyperproliferative and Inflammatory Skin Lesions
Publisher: Elsevier BV
Date: 09-2004
Plzf regulates germline progenitor self-renewal by opposing mTORC1
Publisher: Elsevier BV
Date: 08-2010
Reprogramming can be a transforming experience
Publisher: Elsevier BV
Date: 03-2014
DOI: 10.1016/J.STEM.2014.02.003
Abstract: Since the inception of nuclear reprogramming, the parallels between this process and tumorigenesis have become increasingly apparent. Recent studies by Abad et al. and Ohnishi et al. have now formalized this connection by demonstrating that the same transcription factors used for reprogramming to pluripotency drive tumor initiation in vivo.
Generation of Functional Hepatocytes From Mouse Germ Line Cell-Derived Pluripotent Stem Cells In Vitro
Publisher: Mary Ann Liebert Inc
Date: 08-2010
Abstract: Germ line cell-derived pluripotent stem cells (GPSCs) are similar to embryonic stem (ES) cells in that they can proliferate intensively and differentiate into a variety of cell types. Previous studies have revealed some inherent differences in gene expression between undifferentiated mouse ES cells and GPSCs. Our aims were to generate functional hepatocytes from mouse GPSCs in vitro and to investigate whether the differences in gene expression may impact on the hepatocyte differentiation capacity of the GPSCs compared with ES cells. Mouse GPSCs and ES cells were induced to differentiate into hepatocytes through embryoid body formation, with very high efficiency. These hepatocytes were characterized at cellular, molecular, and functional levels. The GPSC-derived hepatocytes expressed hepatic markers and were metabolically active as shown by albumin and haptoglobin secretion, urea synthesis, glycogen storage, and indocyanine green uptake. We also performed an unprecedented DNA microarray analysis comparing different stages of hepatocyte differentiation. Gene expression profiling demonstrated a strong similarity between GPSC and ES cells at different stages of induced hepatic differentiation. Moreover, Pearson correlation analysis of the microarray datasets suggested that, at late hepatic differentiation stages, the in vitro-derived cells were closer to fetal mouse primary hepatocytes than to those obtained from neonates. We have shown for the first time that adult GPSCs can be induced to differentiate into functional hepatocytes in vitro. These GPSC-derived hepatocytes offer great potential for cell replacement therapy for a wide variety of liver diseases.
Regulation of Interleukin-1α Expression by Integrins and Epidermal Growth Factor Receptor in Keratinocytes from a Mouse Model of Inflammatory Skin Disease
Publisher: Elsevier BV
Date: 05-2003
TCR-inducible PLZF transcription factor required for innate phenotype of a subset of gammadelta T cells with restricted TCR diversity
Publisher: Proceedings of the National Academy of Sciences
Date: 28-07-2009
Abstract: Some γδ and αβ T lymphocytes exhibit an “innate” phenotype associated with rapid cytokine responses. The PLZF transcription factor is essential for the innate phenotype of NKT cells. This report shows that PLZF is likewise responsible for the innate, NKT-like phenotype of Vγ1+Vδ6.3/Vδ6.4+ cells. TCR cross-linking induced PLZF expression in all polyclonal immature γδ thymocytes, suggesting that agonist selection might be required for PLZF induction. Transgenic expression of Vγ1Vδ6.4 TCR was sufficient to support the development of large numbers of PLZF+ T cells, further supporting the importance of the TCR for PLZF induction. Interestingly, expression of this TCR transgene led to the development of spontaneous dermatitis.
Role of the proto-oncogene Pokemon in cellular transformation and ARF repression
Publisher: Springer Science and Business Media LLC
Date: 20-01-2005
DOI: 10.1038/NATURE03203
Abstract: Aberrant transcriptional repression through chromatin remodelling and histone deacetylation has been postulated to represent a driving force underlying tumorigenesis because histone deacetylase inhibitors have been found to be effective in cancer treatment. However, the molecular mechanisms by which transcriptional derepression would be linked to tumour suppression are poorly understood. Here we identify the transcriptional repressor Pokemon (encoded by the Zbtb7 gene) as a critical factor in oncogenesis. Mouse embryonic fibroblasts lacking Zbtb7 are completely refractory to oncogene-mediated cellular transformation. Conversely, Pokemon overexpression leads to overt oncogenic transformation both in vitro and in vivo in transgenic mice. Pokemon can specifically repress the transcription of the tumour suppressor gene ARF through direct binding. We find that Pokemon is aberrantly overexpressed in human cancers and that its expression levels predict biological behaviour and clinical outcome. Pokemon's critical role in cellular transformation makes it an attractive target for therapeutic intervention.
RARα-PLZF overcomes PLZF-mediated repression of CRABPI , contributing to retinoid resistance in t(11;17) acute promyelocytic leukemia
Publisher: Proceedings of the National Academy of Sciences
Date: 20-11-2007
Abstract: Leukemia-associated chimeric oncoproteins often act as transcriptional repressors, targeting promoters of master genes involved in hematopoiesis. We show that CRABPI (encoding cellular retinoic acid binding protein I) is a target of PLZF, which is fused to RARα by the t(11 )(q23 q21) translocation associated with retinoic acid (RA)-resistant acute promyelocytic leukemia (APL). PLZF represses the CRABPI locus through propagation of chromatin condensation from a remote intronic binding element culminating in silencing of the promoter. Although the canonical, PLZF-RARα oncoprotein has no impact on PLZF-mediated repression, the reciprocal translocation product RARα-PLZF binds to this remote binding site, recruiting p300, inducing promoter hypomethylation and CRABPI gene up-regulation. In line with these observations, RA-resistant murine PLZF/RARα+RARα/PLZF APL blasts express much higher levels of CRABPI than standard RA-sensitive PML/RARα APL. RARα-PLZF confers RA resistance to a retinoid-sensitive acute myeloid leukemia (AML) cell line in a CRABPI-dependent fashion. This study supports an active role for PLZF and RARα-PLZF in leukemogenesis, identifies up-regulation of CRABPI as a mechanism contributing to retinoid resistance, and reveals the ability of the reciprocal fusion gene products to mediate distinct epigenetic effects contributing to the leukemic phenotype.
Identification of dynamic undifferentiated cell states within the male germline
Publisher: Springer Science and Business Media LLC
Date: 19-07-2018
DOI: 10.1038/S41467-018-04827-Z
Abstract: The role of stem cells in tissue maintenance is appreciated and hierarchical models of stem cell self-renewal and differentiation often proposed. Stem cell activity in the male germline is restricted to undifferentiated A-type spermatogonia (A undiff ) however, only a fraction of this population act as stem cells in undisturbed testis and A undiff hierarchy remains contentious. Through newly developed compound reporter mice, here we define molecular signatures of self-renewing and differentiation-primed adult A undiff fractions and dissect A undiff heterogeneity by single-cell analysis. We uncover an unappreciated population within the self-renewing A undiff fraction marked by expression of embryonic patterning genes and homeodomain transcription factor PDX1. Importantly, we find that PDX1 marks a population with potent stem cell capacity unique to mature, homeostatic testis and demonstrate dynamic interconversion between PDX1+ and PDX1− A undiff states upon transplant and culture. We conclude that A undiff exist in a series of dynamic cell states with distinct function and provide evidence that stability of such states is dictated by niche-derived cues.
Glucocorticoid-Induced Leucine Zipper (GILZ) Regulates Testicular FOXO1 Activity and Spermatogonial Stem Cell (SSC) Function
Publisher: Public Library of Science (PLoS)
Date: 14-03-2013
Distinctive molecular features of regenerative stem cells in the damaged male germline
Publisher: Springer Science and Business Media LLC
Date: 06-05-2022
DOI: 10.1038/S41467-022-30130-Z
Abstract: Maintenance of male fertility requires spermatogonial stem cells (SSCs) that self-renew and generate differentiating germ cells for production of spermatozoa. Germline cells are sensitive to genotoxic drugs and patients receiving chemotherapy can become infertile. SSCs surviving treatment mediate germline recovery but pathways driving SSC regenerative responses remain poorly understood. Using models of chemotherapy-induced germline damage and recovery, here we identify unique molecular features of regenerative SSCs and characterise changes in composition of the undifferentiated spermatogonial pool during germline recovery by single-cell analysis. Increased mitotic activity of SSCs mediating regeneration is accompanied by alterations in growth factor signalling including PI3K/AKT and mTORC1 pathways. While sustained mTORC1 signalling is detrimental for SSC maintenance, transient mTORC1 activation is critical for the regenerative response. Concerted inhibition of growth factor signalling disrupts core features of the regenerative state and limits germline recovery. We also demonstrate that the FOXM1 transcription factor is a target of growth factor signalling in undifferentiated spermatogonia and provide evidence for a role in regeneration. Our data confirm dynamic changes in SSC functional properties following damage and support an essential role for microenvironmental growth factors in promoting a regenerative state.
SOX3 promotes generation of committed spermatogonia in postnatal mouse testes
Publisher: Springer Science and Business Media LLC
Date: 21-04-2020
DOI: 10.1038/S41598-020-63290-3
Abstract: SOX3 is a transcription factor expressed within the developing and adult nervous system where it mostly functions to help maintain neural precursors. Sox3 is also expressed in other locations, notably within the spermatogonial stem rogenitor cell population in postnatal testis. Independent studies have shown that Sox3 null mice exhibit a spermatogenic block as young adults, the mechanism of which remains poorly understood. Using a panel of spermatogonial cell marker genes, we demonstrate that Sox3 is expressed within the committed progenitor fraction of the undifferentiated spermatogonial pool. Additionally, we use a Sox3 null mouse model to define a potential role for this factor in progenitor cell function. We demonstrate that Sox3 expression is required for transition of undifferentiated cells from a GFRα1+ self-renewing state to the NGN3 + transit- lifying compartment. Critically, using chromatin immunoprecipitation, we demonstrate that SOX3 binds to a highly conserved region in the Ngn3 promoter region in vivo , indicating that Ngn3 is a direct target of SOX3. Together these studies indicate that SOX3 functions as a pro-commitment factor in spermatogonial stem rogenitor cells.
RNA processing in the male germline: Mechanisms and implications for fertility
Publisher: Elsevier BV
Date: 07-2018
DOI: 10.1016/J.SEMCDB.2017.10.006
Abstract: Mammalian spermatogenesis is a tightly coordinated process that gives rise to mature spermatozoa capable of fertilising an ovum during sexual reproduction. A population of stem and progenitor cells known as undifferentiated spermatogonia enables continual spermatogenesis throughout life. A complex transcriptional network that balances self-renewal of spermatogonia with their timely differentiation in order to maintain constant fertility regulates this process. Importantly, post-transcriptional regulation of gene expression plays a critical role in spermatogenesis, necessitated by the profound genetic and morphological changes that occur during meiosis and sperm maturation. Pre-mRNA splicing, mRNA export, maintenance of transcript stability and translation are key RNA processing steps that are regulated in the male germline to maintain coordinated gene expression. In this review, we examine these processes in the context of mammalian spermatogenesis and provide an overview of key mediators at each step.
Identification of the miR-106b ~ 25 MicroRNA Cluster as a Proto-Oncogenic PTEN -Targeting Intron That Coope
Publisher: American Association for the Advancement of Science (AAAS)
Date: 13-04-2010
DOI: 10.1126/SCISIGNAL.2000594
Abstract: A microRNA network regulates the tumor suppressor PTEN in prostate cancer.
Immunology
Publisher: American Association for the Advancement of Science (AAAS)
Date: 11-05-2007
Abstract: Hematopoietic stem cells in the bone marrow give rise to lymphoid progenitors, which subsequently differentiate into B and T lymphocytes. Here we show that the proto-oncogene LRF plays an essential role in the B versus T lymphoid cell-fate decision. We demonstrate that LRF is key for instructing early lymphoid progenitors in mice to develop into B lineage cells by repressing T cell–instructive signals produced by the cell-fate signal protein, Notch. We propose a new model for lymphoid lineage commitment, in which LRF acts as a master regulator of the cell's determination of B versus T lineage.
Distinct germline progenitor subsets defined through Tsc2-mTORC1 signaling
Publisher: EMBO
Date: 19-02-2015
Control of Glucocorticoid Receptor Levels by PTEN Establishes a Failsafe Mechanism for Tumor Suppression
Publisher: Elsevier BV
Date: 10-2020
Shape-shifting and tumor suppression by PLZF
Publisher: Impact Journals, LLC
Date: 04-05-2010
Cyclin-dependent kinase antagonizes promyelocytic leukemia zinc-finger through phosphorylation
Publisher: Springer Science and Business Media LLC
Date: 04-02-2008
DOI: 10.1038/ONC.2008.7
Abstract: Acute promyelocytic leukemia is associated with chromosomal translocations that involve the RARalpha gene and several distinct loci producing a variety of fusion proteins. One such fusion partner is promyelocytic leukemia zinc-finger gene (PLZF), a member of the POK (POZ and Krüppel) family of transcriptional repressors that is a key developmental regulator, stem cell maintenance factor and tumor suppressor. Overexpression of PLZF has been shown to induce cell cycle arrest at the G(1) to S transition and repress the expression of key pro-proliferative genes such as CCNA2 and MYC. However, given this data suggesting an important growth inhibitory role for PLZF, relatively little is known regarding regulation of its activity. Here we show that the main cyclin-dependent kinase involved at the G(1) to S transition (CDK2) phosphorylates PLZF at two consensus sites found within PEST domains present in the hinge region of the protein. This phosphorylation triggers the ubiquitination and subsequent degradation of PLZF, which impairs PLZF transcriptional repression ability and antagonizes its growth inhibitory effects. This critical mechanism of PLZF regulation may thus be relevant for cell cycle progression during the development and the pathogenesis of human cancer.
Systemic Elevation of PTEN Induces a Tumor-Suppressive Metabolic State
Publisher: Elsevier BV
Date: 03-2012
Related Organisations
Memorial Sloan Kettering Cancer Center
Location: United States of America
University Of Oxford
Location: United Kingdom of Great Britain and Northern Ireland
Beth Israel Deaconess Medical Center
Location: United States of America
Related Funding Activities
Discovery Projects - Grant ID: DP140103965
Start Date: 2014
End Date: 12-2017
Amount: $390,000.00
Funder: Australian Research Council
View Funded ActivityARC Future Fellowships - Grant ID: FT140101029
Start Date: 07-2014
End Date: 12-2018
Amount: $771,700.00
Funder: Australian Research Council
View Funded ActivityDiscovery Projects - Grant ID: DP200103463
Start Date: 01-2020
End Date: 01-2023
Amount: $510,000.00
Funder: Australian Research Council
View Funded ActivityDiscovery Projects - Grant ID: DP220103555
Start Date: 07-2022
End Date: 07-2025
Amount: $567,198.00
Funder: Australian Research Council
View Funded ActivitySpecial Research Initiatives - Grant ID: SR1101002
Start Date: 07-2011
End Date: 12-2019
Amount: $21,000,000.00
Funder: Australian Research Council
View Funded Activity