ORCID Profile
0000-0001-7976-8386
Current Organisation
University of Adelaide
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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)
Gene Expression (incl. Microarray and other genome-wide approaches) | Proteomics and Intermolecular Interactions (excl. Medical Proteomics) | Biochemistry and Cell Biology | Biochemistry and Cell Biology not elsewhere classified | Crop and Pasture Improvement (Selection and Breeding) | Cell Development, Proliferation and Death | Animal Nutrition | Crop and Pasture Production
ANZSRC Socio-Economic Objective (SEO)
Expanding Knowledge in the Biological Sciences | Expanding Knowledge in the Agricultural and Veterinary Sciences |
Related Links
Publications
CBFA2T3-ZNF651, like CBFA2T3-ZNF652, functions as a transcriptional corepressor complex.
Publisher: Wiley
Date: 29-01-2010
DOI: 10.1016/J.FEBSLET.2010.01.047
Abstract: A significant proportion of the human genome codes for transcription factors. Balanced activity of transcriptional activators and repressors is essential for normal development and differentiation. Previously we reported that a classical C2H2 zinc finger DNA binding protein ZNF652 functionally interacts with CBFA2T3 to repress transcription of genes containing ZNF652 consensus DNA binding sequence within the promoters of these target genes. Here we show that ZNF651 is a ZNF652 paralogue that shares a common DNA binding sequence with ZNF652 and represses target gene expression through the formation of a CBFA2T3-ZNF651 corepressor complex. It is suggested that CBFA2T3-ZNF651 and CBFA2T3-ZNF652 repressor complexes perform functionally similar roles in a tissue-specific manner.
Dasatinib inhibits the secretion of TNF-a following TLR stimulation in vitro and in vivo
Publisher: Elsevier BV
Date: 12-2009
DOI: 10.1016/J.EXPHEM.2009.09.007
Abstract: Dasatinib (SPRYCEL, BMS-354825) is a small molecule Src/Abl tyrosine kinase inhibitor approved for the treatment of chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. However, kinases inhibited by dasatinib are also involved in the induction and regulation of innate immunity. The purpose of this study was to evaluate the effect of dasatinib on cytokine secretion in response to toll-like receptor (TLR) stimulation. Dasatinib-treated mice were administered intraperitoneally with lipopolysaccharide (LPS) and serum cytokine (tumor necrosis factor-alpha [TNF-alpha], interleukin [IL]-10, and IL-6) levels and neutrophil accumulation in the lungs were analyzed. Cytokine secretions (TNF-alpha and IL-6) from TLR3-, TLR4-, and TLR9-stimulated RAW264.7, as well as TLR4- and TLR9-stimulated bone marrow-derived macrophages (BMDM) were also evaluated. Dasatinib-treated mice had reduced serum levels of TNF-alpha in response to LPS administration however, other inflammatory hallmarks of systemic LPS administration, such as secretion of IL-6 and accumulation of neutrophils in the lung, were unaffected. In contrast to the reduced TNF-alpha levels, dasatinib treatment increased serum levels of IL-10 following LPS administration. The production of TNF-alpha was also impaired in vitro in response to TLR3, TLR4, and TLR9 stimulation of the mouse macrophage cell line RAW264.7, as well as TLR4 and TLR9 stimulation of BMDM IL-6 production was also impaired in dasatinib-treated BMDM. These findings further support the ability of dasatinib to modulate the host immune response and highlights scope for off-target applications of dasatinib for the control of TNF-alpha-mediated inflammatory disorders.
Expanding Clinical Presentations Due to Variations in THOC2 mRNA Nuclear Export Factor.
Publisher: Frontiers Media SA
Date: 11-02-2020
A novel corepressor, BCoR-L1, represses transcription through an interaction with CtBP.
Publisher: Elsevier BV
Date: 05-2007
Abnormal Cell Sorting Underlies the Unique X-Linked Inheritance of PCDH19 Epilepsy
Publisher: Elsevier BV
Date: 2018
DOI: 10.1016/J.NEURON.2017.12.005
Abstract: X-linked diseases typically exhibit more severe phenotypes in males than females. In contrast, protocadherin 19 (PCDH19) mutations cause epilepsy in heterozygous females but spare hemizygous males. The cellular mechanism responsible for this unique pattern of X-linked inheritance is unknown. We show that PCDH19 contributes to adhesion specificity in a combinatorial manner such that mosaic expression of Pcdh19 in heterozygous female mice leads to striking sorting between cells expressing wild-type (WT) PCDH19 and null PCDH19 in the developing cortex, correlating with altered network activity. Complete deletion of PCDH19 in heterozygous mice abolishes abnormal cell sorting and restores normal network activity. Furthermore, we identify variable cortical malformations in PCDH19 epilepsy patients. Our results highlight the role of PCDH19 in determining cell adhesion affinities during cortical development and the way segregation of WT and null PCDH19 cells is associated with the unique X-linked inheritance of PCDH19 epilepsy.
Systematic characterisation of the rat and human CYP24A1 promoter.
Publisher: Elsevier BV
Date: 08-2010
DOI: 10.1016/J.MCE.2010.04.023
Abstract: The biologically active form of vitamin D, 1,25-dihydroxyvitamin D (1,25D) ligands VDR (vitamin D receptor) and binds to the vitamin D response element (VDRE) located within target genes to regulate their transcription. Previously we showed that 1,25D-mediated rat CYP24A1 induction via the two critical VDREs is dependent on a short stretch of nucleotides called vitamin D stimulating element (VSE), located approximately 30bp upstream of VDRE-1 in the rat CYP24A1 promoter. We have now undertaken systematic analysis of the human CYP24A1 and rat CYP24A1 promoters to determine if the VSE is present in the human promoter. Using electrophoretic mobility shift and dual-luciferase reporter assays, we show that the VSE is absent in the human CYP24A1 promoter. In addition, we show that 1,25D-mediated induction of human CYP24A1 is dependant upon a promoter region spanning nucleotides -470 to -392 of the human CYP24A1 promoter.
HUWE1 mutations in Juberg-Marsidi and Brooks syndromes: The results of an X-chromosome exome sequencing study
Publisher: BMJ
Date: 04-2016
Specific-site methylation of tumour suppressor ANKRD11 in breast cancer.
Publisher: Elsevier BV
Date: 11-2012
DOI: 10.1016/J.EJCA.2012.03.023
Abstract: ANKRD11 is a putative tumour suppressor gene in breast cancer, which has been shown in our laboratory to be a co-activator of p53. Our data suggest that down-regulation of ANKRD11 is associated with breast tumourigenesis. Breast cancer cell lines treated with DNA demethylating agents resulted in up-regulation of ANKRD11 expression suggesting that promoter DNA methylation may be responsible for its down-regulation. The transcriptional activity of a CpG-rich region 2kb upstream of the transcription initiation site of ANKRD11 was investigated using dual-luciferase reporter assays. The constructs carrying -661 to -571 bp promoter sequence showed significant transcriptional activity. Using the SEQUENOM Epityper Platform, the region between -770 and +399 bp was analysed in 25 breast tumours, four normal breast tissues and five normal blood s les. The region between -770 and -323 bp was shown to be frequently methylated in breast tumours. The methylation patterns of all analysed CpGs in this region were identical in the normal and tumour s les, except for a 19 bp region containing three CpG sites. These sites had significantly higher levels of methylation in tumours (40%) compared to normal s les (6%). Our findings support the role of ANKRD11 as a tumour suppressor gene and suggest that aberrant DNA methylation of three CpGs in a 19 bp region within the ANKRD11 promoter may be responsible for its down-regulation in breast cancer.
Characterization of the nuclear gene encoding chloroplast ribosomal protein S13 from Arabidopsis thaliana
Publisher: Springer Science and Business Media LLC
Date: 09-1995
DOI: 10.1007/BF00326432
Protocadherin 19 Clustering Epilepsy and Neurosteroids: Opportunities for Intervention.
Publisher: MDPI AG
Date: 09-09-2021
DOI: 10.3390/IJMS22189769
Abstract: Steroids yield great influence on neurological development through nuclear hormone receptor (NHR)-mediated gene regulation. We recently reported that cell adhesion molecule protocadherin 19 (encoded by the PCDH19 gene) is involved in the coregulation of steroid receptor activity on gene expression. PCDH19 variants cause early-onset developmental epileptic encephalopathy clustering epilepsy (CE), with altered steroidogenesis and NHR-related gene expression being identified in these in iduals. The implication of hormonal pathways in CE pathogenesis has led to the investigation of various steroid-based antiepileptic drugs in the treatment of this disorder, with mixed results so far. Therefore, there are many unmet challenges in assessing the antiseizure targets and efficiency of steroid-based therapeutics for CE. We review and assess the evidence for and against the implication of neurosteroids in the pathogenesis of CE and in view of their possible clinical benefit.
Aicardi Syndrome Is a Genetically Heterogeneous Disorder
Publisher: MDPI AG
Date: 31-07-2023
Abstract: Aicardi Syndrome (AIC) is a rare neurodevelopmental disorder recognized by the classical triad of agenesis of the corpus callosum, chorioretinal lacunae and infantile epileptic spasms syndrome. The diagnostic criteria of AIC were revised in 2005 to include additional phenotypes that are frequently observed in this patient group. AIC has been traditionally considered as X-linked and male lethal because it almost exclusively affects females. Despite numerous genetic and genomic investigations on AIC, a unifying X-linked cause has not been identified. Here, we performed exome and genome sequencing of 10 females with AIC or suspected AIC based on current criteria. We identified a unique de novo variant, each in different genes: KMT2B, SLF1, SMARCB1, SZT2 and WNT8B, in five of these females. Notably, genomic analyses of coding and non-coding single nucleotide variants, short tandem repeats and structural variation highlighted a distinct lack of X-linked candidate genes. We assessed the likely pathogenicity of our candidate autosomal variants using the TOPflash assay for WNT8B and morpholino knockdown in zebrafish (Danio rerio) embryos for other candidates. We show expression of Wnt8b and Slf1 are restricted to clinically relevant cortical tissues during mouse development. Our findings suggest that AIC is genetically heterogeneous with implicated genes converging on molecular pathways central to cortical development.
Purification of mitochondria and mitochondrial nucleic acids from embryogenic suspension cultures of a gymnosperm, Larix x leptoeuropaea
Publisher: Springer Science and Business Media LLC
Date: 05-1995
DOI: 10.1007/BF00232790
SCF-FBXO31 E3 ligase targets DNA replication factor Cdt1 for proteolysis in the G2 phase of cell cycle to prevent re-replication.
Publisher: Elsevier BV
Date: 06-2014
Expression of ZNF652, a novel zinc finger protein, in vulvar carcinomas and its relation to prognosis.
Publisher: BMJ
Date: 14-09-2007
Abstract: To determine the levels of expression of ZNF652 and its relevance to prognosis in vulvar squamous cell carcinomas. 22 cases of vulvar intraepithelial neoplasia (VIN) and tumours from 217 patients with vulvar squamous cell carcinomas were investigated for expression of ZNF652 using immunostaining methods. The effect of ZNF652 ectopic expression was determined in the vulvar carcinoma cell line SW954 by western and cell-based assays. High levels of ZNF652 nuclear expression were observed in 5 (100%) of VIN I, 6 (75%) of VIN II and 109 (50.2%) of the vulvar carcinomas, whereas low levels were seen in 2 (25%) VIN II, 9 (100%) of VIN III and 108 (49.8%) of the vulvar carcinomas. High levels of ZNF652 expression in the vulvar carcinomas were significantly correlated to high expression of EphA2. However, when correcting for multiple testing this correlation was lost. No association was identified between ZNF652 expression and p16, p21, p27, p53, cyclin A, D1, D3, E, EphrinA-1 and human papillomavirus. Variations in levels of ZNF652 were not related to prognosis. Low levels of ZNF652 protein were identified in the vulvar carcinoma cell line SW954. Furthermore, SW954 cells ectopically expressing ZNF652 showed reduced cell proliferation and the ability to form colonies on plastic. ZNF652 protein expression is reduced in 25% of VIN II, 100% of VIN III and approximately 50% of the cases of vulvar squamous cell carcinoma, and may be an early event in the pathogenesis of vulvar squamous cell carcinoma. Variations in the levels of ZNF652 were not related to patient's prognosis.
The DUB Club: Deubiquitinating Enzymes and Neurodevelopmental Disorders.
Publisher: Elsevier BV
Date: 10-2022
DOI: 10.1016/J.BIOPSYCH.2022.03.022
Abstract: Protein ubiquitination is a widespread, multifunctional, posttranslational protein modification, best known for its ability to direct protein degradation via the ubiquitin proteasome system (UPS). Ubiquitination is also reversible, and the human genome encodes over 90 deubiquitinating enzymes (DUBs), many of which appear to target specific subsets of ubiquitinated proteins. This review focuses on the roles of DUBs in neurodevelopmental disorders (NDDs). We present the current genetic evidence connecting 12 DUBs to a range of NDDs and the functional studies implicating at least 19 additional DUBs as candidate NDD genes. We highlight how the study of DUBs in NDDs offers critical insights into the role of protein degradation during brain development. Because one of the major known functions of a DUB is to antagonize the UPS, loss of function of DUB genes has been shown to culminate in loss of abundance of its protein substrates. The identification and study of NDD DUB substrates in the developing brain is revealing that they regulate networks of proteins that themselves are encoded by NDD genes. We describe the new technologies that are enabling the full resolution of DUB protein networks in the developing brain, with the view that this knowledge can direct the development of new therapeutic paradigms. The fact that the abundance of many NDD proteins is regulated by the UPS presents an exciting opportunity to combat NDDs caused by haploinsufficiency, because the loss of abundance of NDD proteins can be potentially rectified by antagonizing their UPS-based degradation.
Increased STAG2 dosage defines a novel cohesinopathy with intellectual disability and behavioral problems.
Publisher: Oxford University Press (OUP)
Date: 06-10-2015
DOI: 10.1093/HMG/DDV414
Abstract: Next generation genomic technologies have made a significant contribution to the understanding of the genetic architecture of human neurodevelopmental disorders. Copy number variants (CNVs) play an important role in the genetics of intellectual disability (ID). For many CNVs, and copy number gains in particular, the responsible dosage-sensitive gene(s) have been hard to identify. We have collected 18 different interstitial microduplications and 1 microtriplication of Xq25. There were 15 affected in iduals from 6 different families and 13 singleton cases, 28 affected males in total. The critical overlapping region involved the STAG2 gene, which codes for a subunit of the cohesin complex that regulates cohesion of sister chromatids and gene transcription. We demonstrate that STAG2 is the dosage-sensitive gene within these CNVs, as gains of STAG2 mRNA and protein dysregulate disease-relevant neuronal gene networks in cells derived from affected in iduals. We also show that STAG2 gains result in increased expression of OPHN1, a known X-chromosome ID gene. Overall, we define a novel cohesinopathy due to copy number gain of Xq25 and STAG2 in particular.
THOC2 Mutations Implicate mRNA-Export Pathway in X-Linked Intellectual Disability.
Publisher: Elsevier BV
Date: 08-2015
Nutlin-3a is a potential therapeutic for ewing sarcoma.
Publisher: American Association for Cancer Research (AACR)
Date: 02-2010
DOI: 10.1158/1078-0432.CCR-10-1587
Abstract: Purpose: Although mutations in the TP53 gene occur in half of all cancers, approximately 90% of Ewing sarcomas retain a functional wild-type p53. The low frequency of TP53 alterations in Ewing sarcoma makes this tumor type an ideal candidate for p53-targeted therapies. In this study, we have examined the molecular and cellular responses of cultured Ewing sarcoma cell lines following exposure to Nutlin-3a, a recently developed MDM2 antagonist. Experimental Design: The ability of Nutlin-3a to impart apoptosis or cell cycle arrest in a p53-dependent manner was determined in a comprehensive panel of Ewing sarcoma cell lines. The capacity of Nutlin-3a to augment the antitumor activity of MDM4 antagonists and cytotoxic agents currently used in the clinical treatment of Ewing sarcoma was also investigated. Results: Apoptosis was the primary response of wild-type p53 expressing Ewing sarcoma cell lines. The cytotoxicity of Nultin-3a was also synergistic with the chemotherapeutic agents, vincristine, actinomycin D, doxorubicin, and etoposide in a concentration-dependent manner. Significant MDM4 protein overexpression was observed in Ewing sarcoma cell lines of wild-type p53 status, providing a mechanism through which Ewing sarcomas can develop in the absence of TP53 alterations. This study provides the first evidence of synergism between targeted inhibition of MDM2 and MDM4. Conclusion: Our findings suggest that p53-dependent apoptosis is the primary cellular response of Ewing sarcoma cell lines following exposure to Nutlin-3a. Furthermore, Nutlin-3a can synergize with the current Ewing sarcoma chemotherapy protocols, suggesting p53 activation as a novel systemic therapeutic approach for this disease. Clin Cancer Res 17(3) 494–504. ©2010 AACR.
Kinetics of human immunodeficiency virus type 1 (HIV) DNA integration in acutely infected cells as determined using a novel assay for detection of integrated HIV DNA.
Publisher: American Society for Microbiology
Date: 15-11-2001
DOI: 10.1128/JVI.75.22.11253-11260.2001
Abstract: We have developed a novel linker-primer PCR assay for the detection and quantification of integrated human immunodeficiency virus type 1 (HIV) DNA. This assay reproducibly allowed the detection of 10 copies of integrated HIV DNA, in a background of 2 × 10 5 cell equivalents of human chromosomal DNA, without lifying extrachromosomal HIV DNA. We have used this assay and a near-synchronous one-step T-cell infection model to investigate the kinetics of viral DNA accumulation following HIV infection. We report here that integrated HIV DNA started accumulating 1 h after the first appearance of extrachromosomal viral DNA and accounted for ∼10% of the total HIV DNA synthesized in the first round of viral replication. These results highlight the efficient nature of integrase-mediated HIV integration in infected T cells.
Derepression of an endogenous long terminal repeat activates the CSF1R proto-oncogene in human lymphoma
Publisher: Springer Science and Business Media LLC
Date: 05-2010
DOI: 10.1038/NM.2129
Abstract: Mammalian genomes contain many repetitive elements, including long terminal repeats (LTRs), which have long been suspected to have a role in tumorigenesis. Here we present evidence that aberrant LTR activation contributes to lineage-inappropriate gene expression in transformed human cells and that such gene expression is central for tumor cell survival. We show that B cell-derived Hodgkin's lymphoma cells depend on the activity of the non-B, myeloid-specific proto-oncogene colony-stimulating factor 1 receptor (CSF1R). In these cells, CSF1R transcription initiates at an aberrantly activated endogenous LTR of the MaLR family (THE1B). Derepression of the THE1 subfamily of MaLR LTRs is widespread in the genome of Hodgkin's lymphoma cells and is associated with impaired epigenetic control due to loss of expression of the corepressor CBFA2T3. Furthermore, we detect LTR-driven CSF1R transcripts in anaplastic large cell lymphoma, in which CSF1R is known to be expressed aberrantly. We conclude that LTR derepression is involved in the pathogenesis of human lymphomas, a finding that might have diagnostic, prognostic and therapeutic implications.
HIV type 1 persistence in CD4- /CD8- double negative T cells from patients on antiretroviral therapy.
Publisher: Mary Ann Liebert Inc
Date: 2006
Abstract: The establishment of reservoirs of latently infected cells is thought to contribute to the persistence of HIV-1 infection in the host. Studies so far have mainly focused on the long-lived reservoir of HIV-infected resting CD4+ T cells. A discrete population of HIV-infected CD4-/CD8- double negative (DN) T cells has recently been shown to exist and may also play a role in HIV-1 persistence. DN T cells are CD3 positive, either TCRalphabeta or TCRgammadelta positive, but lack both CD4 and CD8 surface markers. We developed a novel, magnetic bead column-based cell fractionation procedure for isolating >99% pure DN T cells. CD4+, CD8+, and DN T cells were purified from 23 s les of a cohort of 18 HIV-1-infected patients. Each cell fraction was analyzed for levels of total and integrated HIV-1 DNA. A correlation was observed between the presence of HIV-1 DNA in the DN T cell fraction and plasma viral load (VL). Using a micrococulture technique, we saw an initial release of virus from DN T cells of a patient with high VL. Analysis of env and nef sequence data suggested that the HIV-1 present in CD4+ and DN T cells originated from a common infecting strain. Different from the published literature, we have demonstrated the presence of HIV-1 DNA in DN T cells only in patients who are experiencing HAART failure. While these cells may have a limited role in viral persistence in high VL patients, our results suggest DN T cells are unlikely to be a major reservoir in patients on HAART with clinically undetectable plasma viral RNA.
Severe neurocognitive and growth disorders due to variation in THOC2 , an essential component of nuclear mRNA export machinery
Publisher: Hindawi Limited
Date: 14-06-2018
DOI: 10.1002/HUMU.23557
Isozyme studies in Indian mustard (Brassica juncea L.).
Publisher: Springer Science and Business Media LLC
Date: 04-1985
DOI: 10.1007/BF00264491
Evaluation of PCR-based methods for the quantitation of integrated HIV-1 DNA.
Publisher: Elsevier BV
Date: 09-2002
DOI: 10.1016/S0166-0934(02)00105-2
Abstract: Integration of HIV-1 DNA is essential both for productive viral replication and for viral persistence in patients. Methods to measure specifically proviral HIV DNA are required for investigating the mechanisms of HIV integration, for screening novel integrase inhibitors in cell culture and for monitoring levels of persistent integrated viral DNA in patients. In this report, the linker primer polymerase chain reaction (LP-PCR) and Alu-PCR methods for the quantitation of integrated HIV-1 DNA have been modified and evaluated. Each of the two modified assays allowed the quantitative detection of 4 copies of integrated HIV DNA in presence of 2 x 10(5) cell-equivalents of human chromosomal DNA. The results show that proper DNA isolation procedures and the inclusion of appropriate controls in these assays are important for the accurate quantitation of integrated HIV DNA. With further improvements, it should be possible to use these methods as diagnostic tools to monitor closely the efficacy of antiretroviral therapy.
Fbw7α and Fbw7γ collaborate to shuttle cyclin E1 into the nucleolus for multiubiquitylation.
Publisher: Informa UK Limited
Date: 2012
DOI: 10.1128/MCB.00288-12
Variant in the X-chromosome spliceosomal gene GPKOW causes male-lethal microcephaly with intrauterine growth restriction
Publisher: Springer Science and Business Media LLC
Date: 14-06-2017
DOI: 10.1038/EJHG.2017.97
FBXO31 protects against genomic instability by capping FOXM1 levels at the G2/M transition.
Publisher: Springer Science and Business Media LLC
Date: 29-08-2016
DOI: 10.1038/ONC.2016.268
Abstract: F-box proteins in conjunction with Skp1, Cul1 and Rbx1 generate SCF complexes that are responsible for the ubiquitination of proteins, leading to their activation or degradation. Here we show that the F-box protein FBXO31 is required for normal mitotic progression and genome stability due to its role in regulating FOXM1 levels during the G2/M transition. FBXO31-depleted cells undergo a transient delay in mitosis due to an activated spindle checkpoint concomitant with an increase in lagging chromosomes and anaphase bridges. FBXO31 regulates mitosis in part by controlling the levels of FOXM1, a transcription factor and master regulator of mitosis. FBXO31 specifically interacts with FOXM1 during the G2/M transition, resulting in FOXM1 ubiquitination and degradation. FBXO31 depletion results in increased expression of FOXM1 transcriptional targets and mimics the FOXM1 overexpression. In contrast, co-depletion of FBXO31 and FOXM1 restores the genomic instability phenotype but not the delay in mitosis, indicating that FBXO31 probably has additional mitotic substrates. Thus, FBXO31 is the first described negative regulator of FOXM1 during the G2/M transition.
Partial androgen insensitivity syndrome and t(X;5): are there upstream regulatory elements of the androgen receptor gene?
Publisher: S. Karger AG
Date: 2004
DOI: 10.1159/000081064
Abstract: i Background/Aims: /i Two half-brothers with similar malformed genitals, who both inherited a maternally derived t(X )(q13 15) translocation, have a phenotype consistent with partial androgen sensitivity syndrome. The aim was to identify the gene disrupted by the X chromosome breakpoint. i Methods: /i The breakpoint was localized using fluorescence in situ hybridization to metaphase spreads of the translocation. i Results: /i The breakpoint on the X chromosome of the X translocation was localized to a 30-kb region. This region does not contain any identified genes or transcripts. However, the breakpoint is approximately 134 kb from the 5′ end of the androgen receptor i (AR) /i gene. i Conclusions: /i Genetic defects of the i AR /i gene are collectively called androgen insensitivity syndrome and include a range of phenotypes from normal males, often with associated sterility, to XY females. The phenotype seen in the males with the t(X ) is consistent with this syndrome. The analysis of the chromosomal abnormality suggests that this translocation may remove one or more upstream regulatory elements of the i AR /i gene that are essential for its normal expression and its role in typical external masculinization.
Co-expression of the androgen receptor and the transcription factor ZNF652 is related to prostate cancer outcome.
Publisher: Spandidos Publications
Date: 04-03-2010
DOI: 10.3892/OR_00000731
Abstract: ZNF652, a DNA binding transcription factor, was previously suggested to be differentially expressed in prostate cancer. This study investigated if the expressions of ZNF652 and androgen receptor (AR) in prostate cancer are associated with prostate specific antigen (PSA) defined relapse. ZNF652 and AR immunoreactivity were evaluated in prostate tissues from a cohort of 121 patients with prostate cancer and associations with disease outcome determined. To assess if ZNF652 can influence AR expression, or vice versa, levels of expression of ZNF652, AR and PSA were determined in the prostate cell line LNCaP following induction of AR activity by 5alpha-dihydrotestosterone, or knockdown of ZNF652 expression. Two thirds of prostate tumors retained high levels of ZNF652 (71/109 cases) and 50% of tumors high levels of AR (57/113). There was a significant decrease (p=0.005) in relapse-free survival of patients with high expression levels of both ZNF652 and AR and this was independent of preoperative PSA and seminal vesicle involvement. Modulation of either AR or ZNF652 expression levels in LNCaP cells was not associated with any corresponding changes to the levels of either ZNF652 or AR, respectively. High levels of expression of both AR and ZNF652 in clinically organ-defined prostate cancer are associated with a statistically increased risk of relapse. The ZNF652 and AR transcription factors are acting independently and it is proposed that the continued maintenance of expression of ZNF652 in AR positive cells results in a gene expression pattern that contributes to the relapse.
Homozygous mutation of STXBP5L explains an autosomal recessive infantile-onset neurodegenerative disorder
Publisher: Oxford University Press (OUP)
Date: 11-12-2014
DOI: 10.1093/HMG/DDU614
Abstract: We report siblings of consanguineous parents with an infantile-onset neurodegenerative disorder manifesting a predominant sensorimotor axonal neuropathy, optic atrophy and cognitive deficit. We used homozygosity mapping to identify an ∼12-Mbp interval identical by descent (IBD) between the affected in iduals on chromosome 3q13.13-21.1 with an LOD score of 2.31. We combined family-based whole-exome and whole-genome sequencing of parents and affected siblings and, after filtering of likely non-pathogenic variants, identified a unique missense variant in syntaxin-binding protein 5-like (STXBP5L c.3127G>A, p.Val1043Ile [CCDS43137.1]) in the IBD interval. Considering other modes of inheritance, we also found compound heterozygous variants in FMNL3 (c.114G>C, p.Phe38Leu and c.1372T>G, p.Ile458Leu [CCDS44874.1]) located on chromosome 12. STXBP5L (or Tomosyn-2) is expressed in the central and peripheral nervous system and is known to inhibit neurotransmitter release through inhibition of the formation of the SNARE complexes between synaptic vesicles and the plasma membrane. FMNL3 is expressed more widely and is a formin family protein that is involved in the regulation of cell morphology and cytoskeletal organization. The STXBP5L p.Val1043Ile variant enhanced inhibition of exocytosis in comparison with wild-type (WT) STXBP5L. Furthermore, WT STXBP5L, but not variant STXBP5L, promoted axonal outgrowth in manipulated mouse primary hippoc al neurons. However, the FMNL3 p.Phe38Leu and p.Ile458Leu variants showed minimal effects in these cells. Collectively, our clinical, genetic and molecular data suggest that the IBD variant in STXBP5L is the likely cause of the disorder.
Harnessing the complexity of DNA-damage response pathways to improve cancer treatment outcomes.
Publisher: Springer Science and Business Media LLC
Date: 06-09-2010
DOI: 10.1038/ONC.2010.407
Abstract: The DNA-damage response (DDR) pathways consist of interconnected components that respond to DNA damage to allow repair and promote cell survival. The DNA repair pathways and downstream cellular responses have erged in cancer cells compared with normal cells because of genetic alterations that underlie drug resistance, disabled repair and resistance to apoptosis. Consequently, abrogating DDR pathways represents an important mechanism for enhancing the therapeutic index of DNA-damaging anticancer agents. In this review, we discuss the DDR pathways that determine antitumor effects of DNA-damaging agents with a specific focus on treatment outcomes in tumors carrying a defective p53 pathway. Finely tuned survival and death pathways govern the cellular responses downstream of the cytotoxic insults inherent in anticancer treatment. The significance and relative contributions of cellular responses including apoptosis, mitotic catastrophe and senescence are discussed in relation to the web of molecular interactions that affect such outcomes. We propose that promising combinations of DNA-damaging anticancer treatments with DDR-pathway inhibition would be further enhanced by activating downstream apoptotic pathways. The proposed rationale ensures that actual cell death is the preferred outcome of cancer treatment instead of other responses, including reversible cell cycle arrest, autophagy or senescence. Finally, to better measure the contribution of different cellular responses to anticancer treatments, multiplex in vivo assessments of therapy-induced response pathways such as cell death, senescence and mitotic catastrophe is desirable rather than the current reliance on the measurement of a single response pathway such as apoptosis.
RNA editing of larch mitochondrial tRNA(His) precursors is a prerequisite for processing.
Publisher: Oxford University Press (OUP)
Date: 15-08-1996
Abstract: Larch mitochondria contain a'native'tRNAHis which is absent from angiosperms. Sequence comparisons of genomic DNA and cDNA obtained from unprocessed primary transcripts of the larch mitochondrial gene trnH encoding this tRNA revealed three nucleotide discrepancies. These three nucleotide alterations, in the acceptor stem, D stem and anticodon stem respectively, are conversions of genomic cytidines to thymidines in the cDNA (uridines in the tRNA) and thus resemble the RNA editing events observed in nearly all plant mitochondrial mRNAs. Two cases of editing affecting mitochondrial tRNAs from angiosperms have already been described, but we present here the first ex le of such events in a gymnosperm mitochondrial tRNA. All three editing events correct mismatched C x A base pairs which appear when folding the gene sequence into the standard cloverleaf structure, thereby improving the secondary structure of the tRNA. When incubated with a heterologous potato mitochondrial processing extract, only the edited form of the larch mitochondrial tRNAHis precursor was efficiently processed in vitro. These data strongly suggest that editing of larch mitochondrial tRNAHis is a prerequisite for its processing.
Effect of deletion and the site of insertion in double copy anti-tat retroviral vectors: viral titres and production of anti-tat mRNA.
Publisher: Springer Science and Business Media LLC
Date: 11-2001
Abstract: In attempts to further develop murine leukemia virus (MLV) based retroviral vectors for gene therapy, we investigated vector production and antisense expression from retroviral constructs with U3 deletions or insertions. Promoter elements in the U3 region of the 3' LTR of the vector pLXSN were deleted and replaced with DNA encoding the HIV anti-tat gene under control of the tRNAmet promoter to produce a double copy self inactivating vector (DC-SIN). DC-SIN constructs were compared to vectors containing the anti-tat cassette inserted at 5 different sites of the U3 region (DC-insertions). Titres of DC-SIN and DC-insertion vectors were similar but approximately 10 fold lower than parental pLXSN. Cells transduced with DC-SIN and DC-insertion vectors all expressed anti-tat mRNA. Transcripts from the MLV-LTR were detected in cells transduced with DC-insertion but not DC-SIN vectors or a vector with the anti-tat cassette between CAAT and TATA boxes of the promoter, indicating inactivation of the viral promoter in the latter vectors. Cells transduced with constructs of either design showed comparable efficacy of protection against HIV challenge. Thus, no U3 insertion site was preferred for virus production. Insertion of a tRNA promoter between CAAT and TATA boxes and the DC-SIN design which would not introduce an active RNA pol II promoter into the genome are attractive for further development of safe gene therapy agents.
Protocadherin 19 (PCDH19) interacts with paraspeckle protein NONO to co-regulate gene expression with estrogen receptor alpha (ERα)
Publisher: Oxford University Press (OUP)
Date: 17-03-2017
DOI: 10.1093/HMG/DDX094
The application of delivery systems for DNA methyltransferase inhibitors.
Publisher: Springer Science and Business Media LLC
Date: 08-2011
DOI: 10.2165/11592770-000000000-00000
Abstract: DNA methylation, which often occurs at the cytosine residue of cytosine-guanine dinucleotides, is critical for the control of gene expression and mitotic inheritance in eukaryotes. DNA methylation silences gene expression either by directly hindering the access of transcription factors to the target DNA, or through recruitment of histone deacetylases to remodel the chromatin structure to an inactive state. Aberrant hypermethylation of tumor suppressor genes is commonly associated with the development of cancer. A number of anti-cancer agents have been developed that function through demethylation, reversing regional hypermethylation to restore the expression of tumor suppressor genes. Azacitidine and decitabine are used in the clinic, but their applications are limited to myelodysplastic syndrome and other blood-related diseases. Despite the potency of these drugs, their broader clinical application is restricted by cytotoxicity, nonspecific targeting, structural instability, catabolism, and poor bioavailability. Further improvements in the delivery systems for these drugs could overcome the issues associated with inefficient bioavailability, whilst facilitating the administration of combinations of demethylating agents and histone deacetylase inhibitors to enhance efficacy. This review focuses on the current limitations of existing demethylating agents and highlights possible approaches using recent developments in drug delivery systems to improve the clinical potential of these drugs.
Heme carrier protein 1 (HCP1) expression and functional analysis in the retina and retinal pigment epithelium.
Publisher: Elsevier BV
Date: 04-2007
DOI: 10.1016/J.YEXCR.2007.01.019
Abstract: The retina and retinal pigment epithelium (RPE) are present in the posterior segment of the eye, and the retina is dependent upon the underlying RPE for normal function. The retina is the most oxygenated tissue in the body but is isolated from the blood circulation by blood-retinal barriers. Metabolism of cellular oxygen involves heme but little is known about heme transport in the retina and RPE. Here we report the identification from bovine RPE of a heme transporter bHcp1 (bovine heme carrier protein 1) that is homologous to mouse intestinal HCP1 expressed in duodenal enterocytes. Similar to the mouse protein, bHcp1 exhibited heme uptake ability in Xenopus oocytes and localized to the cell membrane in cultured mammalian epithelium. Whereas bHcp1 expression was detected only in bovine RPE, expression of its human homologue was identified in both retina and RPE. Furthermore, the data revealed low-level wider expression of human HCP1 transcript in multiple tissues suggesting that it is responsible for heme transport in the body, not the intestine alone. Expression of HCP1 in the RPE and retina indicates the mechanism of heme transport in these ocular tissues.
Mutant p53 drives invasion in breast tumors through up-regulation of miR-155
Publisher: Springer Science and Business Media LLC
Date: 16-07-2012
DOI: 10.1038/ONC.2012.305
Abstract: Loss of p53 function is a critical event during tumorigenesis, with half of all cancers harboring mutations within the TP53 gene. Such events frequently result in the expression of a mutated p53 protein with gain-of-function properties that drive invasion and metastasis. Here, we show that the expression of miR-155 was up-regulated by mutant p53 to drive invasion. The miR-155 host gene was directly repressed by p63, providing the molecular basis for mutant p53 to drive miR-155 expression. Significant overlap was observed between miR-155 targets and the molecular profile of mutant p53-expressing breast tumors in vivo. A search for cancer-related target genes of miR-155 revealed ZNF652, a novel zinc-finger transcriptional repressor. ZNF652 directly repressed key drivers of invasion and metastasis, such as TGFB1, TGFB2, TGFBR2, EGFR, SMAD2 and VIM. Furthermore, silencing of ZNF652 in epithelial cancer cell lines promoted invasion into matrigel. Importantly, loss of ZNF652 expression in primary breast tumors was significantly correlated with increased local invasion and defined a population of breast cancer patients with metastatic tumors. Collectively, these findings suggest that miR-155 targeted therapies may provide an attractive approach to treat mutant p53-expressing tumors.
Abstracts from the 53rd European Society of Human Genetics (ESHG) Conference: Oral Presentations
Publisher: Springer Science and Business Media LLC
Date: 12-2020
Integrated in silico and experimental assessment of disease relevance of PCDH19 missense variants.
Publisher: Hindawi Limited
Date: 15-06-2021
DOI: 10.1002/HUMU.24237
Abstract: PCDH19 is a nonclustered protocadherin molecule involved in axon bundling, synapse function, and transcriptional coregulation. Pathogenic variants in PCDH19 cause infantile-onset epilepsy known as PCDH19-clustering epilepsy or PCDH19-CE. Recent advances in DNA-sequencing technologies have led to a significant increase in the number of reported PCDH19-CE variants, many of uncertain significance. We aimed to determine the best approaches for assessing the disease relevance of missense variants in PCDH19. The application of the American College of Medical Genetics and Association for Molecular Pathology (ACMG-AMP) guidelines was only 50% accurate. Using a training set of 322 known benign or pathogenic missense variants, we identified MutPred2, MutationAssessor, and GPP as the best performing in silico tools. We generated a protein structural model of the extracellular domain and assessed 24 missense variants. We also assessed 24 variants using an in vitro reporter assay. A combination of these tools was 93% accurate in assessing known pathogenic and benign PCDH19 variants. We increased the accuracy of the ACMG-AMP classification of 45 PCDH19 variants from 50% to 94%, using these tools. In summary, we have developed a robust toolbox for the assessment of PCDH19 variant pathogenicity to improve the accuracy of PCDH19-CE variant classification.
Forkhead transcription factors, Fkh1p and Fkh2p, collaborate with Mcm1p to control transcription required for M-phase.
Publisher: Elsevier BV
Date: 08-2000
DOI: 10.1016/S0960-9822(00)00618-7
Abstract: The 'CLB2 cluster' in Saccharomyces cerevisiae consists of approximately 33 genes whose transcription peaks in late G2/early M phase of the cell cycle. Many of these genes are required for execution of the mitotic program and then for cytokinesis. The transcription factor SFF (SWI5 factor) is thought to regulate a program of mitotic transcription in conjunction with the general transcription factor Mcm1p. The identity of SFF has yet to be determined hence further understanding of the mechanisms that regulate entry to M phase at the transcriptional level requires characterization of SFF at the molecular level. We have purified the biochemical activity corresponding to SFF and identified it as the forkhead transcription factor Fkh2p. Fkh2p assembles into ternary complexes with Mcm1p on both the SWI5 and CLB2 cell-cycle-regulated upstream activating sequence (UAS) elements in vitro, and in an Mcm1 p-dependent manner in vivo. Another closely related forkhead protein, Fkh1p, is also recruited to the CLB2 promoter in vivo. We show that both FKH1 and FKH2 play essential roles in the activation of the CLB2 cluster genes during G2-M and in establishing their transcriptional periodicity. Hence, Fkh1p and Fkhp2 show the properties expected of SFF, both in vitro and in vivo. Forkhead transcription factors have redundant roles in the control of CLB2 cluster genes during the G2-M period of the cell cycle, in collaboration with Mcm1p.
Development of a novel cell-based assay system EPISSAY for screening epigenetic drugs and liposome formulated decitabine
Publisher: Springer Science and Business Media LLC
Date: 13-03-2013
FBXO31 is the chromosome 16q24.3 senescence gene, a candidate breast tumor suppressor, and a component of an SCF complex.
Publisher: American Association for Cancer Research (AACR)
Date: 15-12-2005
DOI: 10.1158/0008-5472.CAN-05-0936
Abstract: A BAC located in the 16q24.3 breast cancer loss of heterozygosity region was previously shown to restore cellular senescence when transferred into breast tumor cell lines. We have shown that FBXO31, although located just distal to this BAC, can induce cellular senescence in the breast cancer cell line MCF-7 and is the likely candidate senescence gene. FBXO31 has properties consistent with a tumor suppressor, because ectopic expression of FBXO31 in two breast cancer cell lines inhibited colony growth on plastic and inhibited cell proliferation in the MCF-7 cell line. In addition, compared with the relative expression in normal breast, levels of FBXO31 were down-regulated in breast tumor cell lines and primary tumors. FBXO31 was cell cycle regulated in the breast cell lines MCF-10A and SKBR3 with maximal expression from late G2 to early G1 phase. Ectopic expression of FBXO31 in the breast cancer cell line MDA-MB-468 resulted in the accumulation of cells at the G1 phase of the cell cycle. FBXO31 contains an F-box domain and is associated with the proteins Skp1, Roc-1, and Cullin-1, suggesting that FBXO31 is a component of a SCF ubiquitination complex. We propose that FBXO31 functions as a tumor suppressor by generating SCFFBXO31 complexes that target particular substrates, critical for the normal execution of the cell cycle, for ubiquitination and subsequent degradation. (Cancer Res 2005 65(24): 11304-313)
Mutations in USP9X are associated with X-linked intellectual disability and disrupt neuronal cell migration and growth.
Publisher: Elsevier BV
Date: 03-2014
Mutant p53 drives multinucleation and invasion through a process that is suppressed by ANKRD11
Publisher: Springer Science and Business Media LLC
Date: 10-10-2012
DOI: 10.1038/ONC.2011.456
Abstract: Mutations of p53 in cancer can result in a gain of function associated with tumour progression and metastasis. We show that inducible expression of several p53 'hotspot' mutants promote a range of centrosome abnormalities, including centrosome lification, increased centrosome size and loss of cohesion, which lead to mitotic defects and multinucleation. These mutant p53-expressing cells also show a change in morphology and enhanced invasive capabilities. Consequently, we sought for a means to specifically target the function of mutant p53 in cancer cells. This study has identified ANKRD11 as a key regulator of the oncogenic potential of mutant p53. Loss of ANKRD11 expression with p53 mutation defines breast cancer patients with poor prognosis. ANKRD11 alleviates the mitotic defects driven by mutant p53 and suppresses mutant p53-mediated mesenchymal-like transformation and invasion. Mechanistically, we show that ANKRD11 restores a native conformation to the mutant p53 protein and causes dissociation of the mutant p53-p63 complex. This represents the first evidence of an endogenous protein with the capacity to suppress the oncogenic properties of mutant p53.
Striking differences in mitochondrial tRNA import between different plant species.
Publisher: Springer Science and Business Media LLC
Date: 09-1996
DOI: 10.1007/BF02173005
CBFA2T3-ZNF652 corepressor complex regulates transcription of the E-box gene HEB.
Publisher: Elsevier BV
Date: 07-2008
Oligonucleotide correction of an intronic TIMMDC1 variant in cells of patients with severe neurodegenerative disorder.
Publisher: Springer Science and Business Media LLC
Date: 28-01-2022
DOI: 10.1038/S41525-021-00277-7
Abstract: TIMMDC1 encodes the T ranslocase of I nner M itochondrial M embrane D omain- C ontaining protein 1 (TIMMDC1) subunit of complex I of the electron transport chain responsible for ATP production. We studied a consanguineous family with two affected children, now deceased, who presented with failure to thrive in the early postnatal period, poor feeding, hypotonia, peripheral neuropathy and drug-resistant epilepsy. Genome sequencing data revealed a known, deep intronic pathogenic variant TIMMDC1 c.597-1340A G, also present in gnomAD (~1/5000 frequency), that enhances aberrant splicing. Using RNA and protein analysis we show almost complete loss of TIMMDC1 protein and compromised mitochondrial complex I function. We have designed and applied two different splice-switching antisense oligonucleotides (SSO) to restore normal TIMMDC1 mRNA processing and protein levels in patients’ cells. Quantitative proteomics and real-time metabolic analysis of mitochondrial function on patient fibroblasts treated with SSOs showed restoration of complex I subunit abundance and function. SSO-mediated therapy of this inevitably fatal TIMMDC1 neurologic disorder is an attractive possibility.
RNA editing of a chimeric maize mitochondrial gene transcript is sequence specific.
Publisher: Springer Science and Business Media LLC
Date: 02-1993
DOI: 10.1007/BF00352015
Abstract: Latin American societies show lower levels of political trust when compared to other regions of the world. The lack of trust in institutions can led to ineffective management of public affairs, social crises, lack of transparency, economic problems and even difficulties in countering pandemics. The objective of this work is to build an index (LADI) that provides a measure of the level of perceived distrust in the institutions of the different Latin American countries and its variations over the period from 2008 to 2018. The data used for this analysis are of a subjective nature and come from the series of surveys provided by
Genome-wide mapping of ZNF652 promoter binding sites in breast cancer cells.
Publisher: Wiley
Date: 19-09-2011
DOI: 10.1002/JCB.23214
Abstract: A significant proportion of transcription factors encoded by the human genome are classical C(2) H(2) zinc finger proteins that regulate gene expression by directly interacting with their cognate DNA binding motifs. We previously showed that one such C(2) H(2) zinc finger DNA binding protein, ZNF652 (zinc finger protein 652), specifically and functionally interacts with CBFA2T3 to repress transcription of genes involved in breast oncogenesis. To identify potential targets by which ZNF652 exerts its putative tumour suppressive function, its promoter-specific cistrome was mapped by ChIP-chip. De novo motif scanning of the ZNF652 binding sites identified a novel ZNF652 recognition motif that closely resembles the previously characterised in vitro binding site, being a 10 nucleotide core of that 13 nucleotide sequence. Genes with ZNF652 binding sites function in erse cellular pathways, and many are involved in cancer development and progression. Characterisation of the in vivo ZNF652 DNA binding motif and identification of potential ZNF652 target genes are key steps towards elucidating the function(s) of this transcription factor in the normal and malignant breast cell.
A noncoding, regulatory mutation implicates HCFC1 in nonsyndromic intellectual disability.
Publisher: Elsevier BV
Date: 10-2012
Clinical and functional characterization of recurrent missense variants implicated in THOC6-related intellectual disability.
Publisher: Oxford University Press (OUP)
Date: 21-11-2019
DOI: 10.1093/HMG/DDY391
Abstract: THOC6 encodes a subunit of the THO complex that is part of a highly conserved transcription and export complex known to have roles in mRNA processing and export. Few homozygous or compound heterozygous variants have been identified in the THOC6 gene in patients with a syndromic form of intellectual disability [Beaulieu-Boycott-Innes syndrome (BBIS) MIM: 613680]. Here we report two additional in iduals affected with BBIS originating from the north of Europe and sharing a haplotype composed of three very rare missense changes in the THOC6 gene-Trp100Arg, Val234Leu, Gly275Asp. The first in idual is a boy who is homozygous for the three-variant haplotype due to a maternal uniparental disomy event. The second is a girl who is compound heterozygous for this haplotype and a previously reported Gly190Glu missense variant. We analyzed the impact of these different amino acid changes on THOC6 protein expression, cellular localization and interaction with the other THO complex subunits. We show that the different THOC6 variants alter the physiological nuclear localizationof the protein and its interaction with at least two THO subunits, THOC1 and THOC5. Two amino acid changes from the three-variant haplotype alone have specific effects and might contribute to the pathogenicity of the haplotype. Overall, we expanded the cohort of currently known in iduals with BBIS by reporting two in iduals carrying the same recurrent European haplotype composed of three amino acid changes, affecting THOC6 localization and interaction with THO protein partners.
Specific inhibition of human immunodeficiency virus type 1 (HIV-1) integration in cell culture: putative inhibitors of HIV-1 integrase.
Publisher: American Society for Microbiology
Date: 09-2001
DOI: 10.1128/AAC.45.9.2510-2516.2001
Abstract: To study the effect of potential human immunodeficiency virus type 1 (HIV-1) integrase inhibitors during virus replication in cell culture, we used a modified nested Alu-PCR assay to quantify integrated HIV DNA in combination with the quantitative analysis of extrachromosomal HIV DNA. The two diketo acid integrase inhibitors (L-708,906 and L-731,988) blocked the accumulation of integrated HIV-1 DNA in T cells following infection but did not alter levels of newly synthesized extrachromosomal HIV DNA. In contrast, we demonstrated that L17 (a member of the bisaroyl hydrazine family of integrase inhibitors) and AR177 (an oligonucleotide inhibitor) blocked the HIV replication cycle at, or prior to, reverse transcription, although both drugs inhibited integrase activity in cell-free assays. Quercetin dihydrate (a flavone) was shown to not have any antiviral activity in our system despite reported anti-integration properties in cell-free assays. This refined Alu-PCR assay for HIV provirus is a useful tool for screening anti-integration compounds identified in biochemical assays for their ability to inhibit the accumulation of integrated HIV DNA in cell culture, and it may be useful for studying the effects of these inhibitors in clinical trials.
Two novel intragenic variants in the FMR1 gene in patients with suspect clinical diagnosis of Fragile X syndrome and no CGG repeat expansion.
Publisher: Elsevier BV
Date: 10-2020
Endogenous protein interactomes resolved through immunoprecipitation-coupled quantitative proteomics in cell lines.
Publisher: Elsevier BV
Date: 12-2022
Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID.
Publisher: Springer Science and Business Media LLC
Date: 24-02-2015
DOI: 10.1038/MP.2015.5
Molecular and functional characterization of a novel low-affinity cation transporter (LCT1) in higher plants.
Publisher: Proceedings of the National Academy of Sciences
Date: 30-09-1997
Abstract: The transport of cations across membranes in higher plants plays an essential role in many physiological processes including mineral nutrition, cell expansion, and the transduction of environmental signals. In higher plants the coordinated expression of transport mechanisms is essential for specialized cellular processes and for adaptation to variable environmental conditions. To understand the molecular basis of cation transport in plant roots, a Triticum aestivum cDNA library was used to complement a yeast mutant deficient in potassium (K + ) uptake. Two genes were cloned that complemented the mutant: HKT1 and a novel cDNA described in this report encoding a cation transporter, LCT1 (low-affinity cation transporter). Analysis of the secondary structure of LCT1 suggests that the protein contains 8–10 transmembrane helices and a hydrophilic amino terminus containing sequences enriched in Pro, Ser, Thr, and Glu (PEST). The transporter activity was assayed using radioactive isotopes in yeast cells expressing the cDNA. LCT1 mediated low-affinity uptake of the cations Rb + and Na + , and possibly allowed Ca 2+ but not Zn 2+ uptake. LCT1 is expressed in low abundance in wheat roots and leaves. The precise functional role of this cation transporter is not known, although the competitive inhibition of cation uptake by Ca 2+ has parallels to whole plant and molecular studies that have shown the important role of Ca 2+ in reducing Na + uptake and ameliorating Na + toxicity. The structure of this higher plant ion transport protein is unique and contains PEST sequences.
Identification of ANKRD11 as a p53 coactivator
Publisher: The Company of Biologists
Date: 11-2008
DOI: 10.1242/JCS.026351
Abstract: The ability of p53 to act as a transcription factor is critical for its function as a tumor suppressor. Ankyrin repeat domain 11, ANKRD11 (also known as ANR11 or ANCO1), was found to be a novel p53-interacting protein that enhanced the transcriptional activity of p53. ANKRD11 expression was shown to be downregulated in breast cancer cell lines. Restoration of ANKRD11 expression in MCF-7 (wild-type p53) and MDA-MB-468 (p53R273H mutant) cells suppressed their proliferative and clonogenic properties through enhancement of CDKN1A (p21waf1/CIP1) expression. ShRNA-mediated silencing of ANKRD11 expression reduced the ability of p53 to activate CDKN1A expression. ANKRD11 was shown to associate with the p53 acetyltransferases and cofactors, P/CAF and hADA3. Exogenous ANKRD11 expression enhanced the levels of acetylated p53 in both MCF-7 and MDA-MB-468 cells. ANKRD11 enhanced the DNA-binding properties of mutant p53R273H to the CDKN1A promoter, suggesting that ANKRD11 can mediate the restoration of normal p53 function in some cancer-related p53 mutations. In addition, ANKRD11 itself was found to be a novel p53 target gene. These findings demonstrate a role for ANKRD11 as a p53 coactivator and suggest the involvement of ANKRD11 in a regulatory feedback loop with p53.
A standardized patient-centered characterization of the phenotypic spectrum of PCDH19 girls clustering epilepsy
Publisher: Springer Science and Business Media LLC
Date: 04-05-2020
DOI: 10.1038/S41398-020-0803-0
Abstract: Protocadherin-19 ( PCDH19 ) pathogenic variants cause an early-onset seizure disorder called girls clustering epilepsy (GCE). GCE is an X-chromosome disorder that affects heterozygous females and mosaic males, however hemizygous (“transmitting”) males are spared. We aimed to define the neuropsychiatric profile associated with PCDH19 pathogenic variants and determine if a clinical profile exists for transmitting males. We also examined genotype- and phenotype–phenotype associations. We developed an online PCDH19 survey comprising the following standardized assessments: The Behavior Rating Inventory of Executive Function the Social Responsiveness Scale, 2nd edition the Strengths and Difficulties Questionnaire and the Dimensional Obsessive-Compulsive Scale. Genetic, seizure, and developmental information were also collected. The survey was completed by patients or by caregivers on behalf of patients. Of the 112 in iduals represented (15 males), there were 70 unique variants. Thirty-five variants were novel and included a newly identified recurrent variant Ile781Asnfs*3. There were no significant differences in phenotypic outcomes between published and unpublished cases. Seizures occurred in clusters in 94% of in iduals, with seizures resolving in 28% at an average age of 17.5 years. Developmental delay prior to seizure onset occurred in 18% of our cohort. Executive dysfunction and autism spectrum disorder (ASD) occurred in approximately 60% of in iduals. The ASD profile included features of attention-deficit hyperactivity disorder. In addition, 21% of in iduals met criteria for obsessive-compulsive disorder that appeared to be distinct from ASD. There were no phenotypic differences between heterozygous females and mosaic males. We describe a mosaic male and two hemizygous males with atypical clinical profiles. Earlier seizure onset age and increased number of seizures within a cluster were associated with more severe ASD symptoms ( p = 0.001), with seizure onset also predictive of executive dysfunction ( p = 4.69 × 10 −4 ) and prosocial behavior ( p = 0.040). No clinical profile was observed for transmitting males. This is the first patient-derived standardized assessment of the neuropsychiatric profile of GCE. These phenotypic insights will inform diagnosis, management, and prognostic and genetic counseling.
Mutations of protocadherin 19 in female epilepsy (PCDH19-FE) lead to allopregnanolone deficiency.
Publisher: Oxford University Press (OUP)
Date: 29-06-2015
DOI: 10.1093/HMG/DDV245
Abstract: Protocadherin 19 (PCDH19) female limited epilepsy (PCDH19-FE also known as epilepsy and mental retardation limited to females, EFMR MIM300088) is an infantile onset epilepsy syndrome with or without intellectual disability (ID) and autism. We investigated transcriptomes of PCDH19-FE female and control primary skin fibroblasts, which are endowed to metabolize neurosteroid hormones. We identified a set of 94 significantly dysregulated genes in PCDH19-FE females. Intriguingly, 43 of the 94 genes (45.7%) showed gender-biased expression enrichment of such genes was highly significant (P = 2.51E-47, two-tailed Fisher exact test). We further investigated the AKR1C1-3 genes, which encode crucial steroid hormone-metabolizing enzymes whose key products include allopregnanolone and estradiol. Both mRNA and protein levels of AKR1C3 were significantly decreased in PCDH19-FE patients. In agreement with this, the blood levels of allopregnanolone were also (P < 0.01) reduced. In conclusion, we show that the deficiency of neurosteroid allopregnanolone, one of the most potent GABA receptor modulators, may contribute to PCDH19-FE. Overall our findings provide evidence for a role of neurosteroids in epilepsy, ID and autism and create realistic opportunities for targeted therapeutic interventions.
A Recurrent De Novo Nonsense Variant in ZSWIM6 Results in Severe Intellectual Disability without Frontonasal or Limb Malformations
Publisher: Elsevier BV
Date: 12-2017
Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor β Signaling
Publisher: Elsevier BV
Date: 2020
Site directed mutagenesis reduces the Na+ affinity of HKT1, an Na+ energized high affinity K+ transporter.
Publisher: Wiley
Date: 31-07-1998
DOI: 10.1016/S0014-5793(98)00833-3
Abstract: HKT1 encodes a high affinity Na+ coupled K+ transporter expressed in the cortical cells of Triticum aestivum roots. To identify regions of the protein involved in the binding and transport of Na+ and K+, mutations were introduced into a domain of HKT1 containing 16 amino acids that are highly conserved across a range of putative K+ transport proteins from different phyla. Two mutations had a significant effect on the functional characteristics of the transporter. A yeast growth assay showed that concentrations of NaCl between 2.5 to 50 mM stimulated the growth of yeast expressing HKT1 containing the E464Q substitution, but not the growth of yeast expressing HKT1. Kinetic analysis confirmed that the E464Q mutation lowered the affinity of HKT1 for Na+ but did not affect its affinity for K+. A second mutation in the same region F463L was created that also lowered the affinity of the transporter for Na+. The importance of these highly conserved amino acid residues is highlighted by the fact that they have remained conserved through evolution. The results of this mutational analysis suggest that this domain in HKT1 plays a role in the binding and transport of Na+.
ZNF652, a novel zinc finger protein, interacts with the putative breast tumor suppressor CBFA2T3 to repress transcription.
Publisher: American Association for Cancer Research (AACR)
Date: 09-2006
DOI: 10.1158/1541-7786.MCR-05-0249
Abstract: The transcriptional repressor CBFA2T3 is a putative breast tumor suppressor. To define the role of CBFA2T3, we used a segment of this protein as bait in a yeast two-hybrid screen and identified a novel uncharacterized protein, ZNF652. In general, primary tumors and cancer cell lines showed lower expression of ZNF652 than normal tissues. Together with the location of this gene on the long arm of chromosome 17q, a region of frequent loss of heterozygosity in cancer, these results suggest a possible role of ZNF652 in tumorigenesis. In silico analysis of this protein revealed that it contains multiple classic zinc finger domains that are predicted to bind DNA. Coimmunoprecipitation assays showed that ZNF652 strongly interacts with CBFA2T3 and this interaction occurs through the COOH-terminal 109 amino acids of ZNF652. In contrast, there was a weak interaction of ZNF652 with CBFA2T1 and CBFA2T2, the other two members of this ETO family. Transcriptional reporter assays further confirmed the strength and selectivity of the ZNF652-CBFA2T3 interaction. The transcriptional repression of growth factor independent-1 (GFI-1), a previously characterized ETO effector zinc finger protein, was shown to be enhanced by CBFA2T1, but to a lesser extent by CBFA2T2 and CBFA2T3. We therefore suggest that each of the various gene effector zinc finger proteins may specifically interact with one or more of the ETO proteins to generate a defined range of transcriptional repressor complexes. (Mol Cancer Res 2006 (9):655–65)
YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction.
Publisher: Elsevier BV
Date: 06-2017
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