HoxC5 and Pbx4 repress hTERT to limit telomerase activity
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE97570 | GEO | 2018/02/13
REPOSITORIES: GEO
Similar Datasets
Project description:Telomerase controls cell immortality and is a promising cancer target. Understanding transcriptional regulation of the catalytic subunit hTERT is critical to realise effective telomerase therapeutics. GSK3 inhibition suppresses hTERT expression.
2009-08-03 | GSE14532 | GEO
Project description:The catalytic subunit of the human telomerase (hTERT) is activated during tumorigenesis in many cancers including prostate cancer (PCa). Androgens mediate their effect through the androgen receptor (AR), a key factor controlling PCa growth. hTERT expression is known to be regulated by androgens, however contrarily observed to be inhibited or activated. Here, we reveal that androgens repress or activate hTERT expression in a concentration-dependent manner. Low physiological androgen levels activate while supraphysiological androgen levels (SAL) repress hTERT expression. We confirmed SAL-mediated gene repression of hTERT in native human PCa samples derived from patients treated ex vivo as well as in cancer spheroids derived from androgen-dependent and castration resistant PCa (CRPC) cells. Interestingly, based on chromatin immunoprecipitation (ChIP) data both a positive androgen response element (pARE) at -4kb distal and a negative response element (nARE) at the proximal -0.1kb promoter region were identified. Focusing on the nARE it was narrowed down to -121 to -58 bp in the core promoter region. ChIP experiments confirmed an androgen-dependent recruitment of AR and the tumor suppressors inhibitor of growth 1 and 2 (ING1 and ING2), recently identified as AR co-repressors. Mechanistically, the knockdown of either ING1 or ING2 reduced androgen-mediated repression of hTERT indicating that ING1 and ING2 mediate AR-regulated transrepression on the hTERT expression. Thus, our data suggest a dual, biphasic function of AR to control hTERT expression by transactivation and transrepression. The inhibition of hTERT by androgens by a nARE located in the proximal promoter region is mediated at least in part by the AR co-repressors ING1 and ING2.
2022-03-04 | GSE155528 | GEO
Project description:A gene expression signature classifying telomerase and ALT immortalisation reveals an hTERT regulatory network and suggests a mesenchymal stem cell origin for ALT Telomere length is maintained by 2 known mechanisms, activation of telomerase or alternative lengthening of telomeres (ALT). The molecular mechanisms regulating the ALT phenotype are poorly understood and it is unknown how the decision of which pathway to activate is made at the cellular level. We have shown previously that active repression of telomerase gene expression by chromatin remodelling of the promoters is one mechanism of regulation, however other genes and signalling networks are likely to be required to regulate telomerase and maintain the ALT phenotype. Using gene expression profiling we have uncovered a signature of 1305 genes to distinguish telomerase positive and ALT cell lines. By combining this with gene expression profiles of liposarcoma tissue samples we refined this signature to 297 genes significantly associated with telomere maintenance mechanism. Network analysis of known direct interactions between genes within this signature revealed a regulatory signalling network consistent with a model of hTERT repression in ALT cell lines and liposarcomas. This network expands on our existing knowledge of hTERT regulation and provides a platform to understand differential regulation of hTERT in different tumour types and normal tissues. In addition we show evidence to suggest a novel mesenchymal stem cell origin for ALT immortalisation in cell lines and mesenchymal tissues. Keywords: cell type comparison, gene expression
2009-11-02 | GSE14487 | GEO
Project description:A gene expression signature classifying telomerase and ALT immortalisation reveals an hTERT regulatory network and suggests a mesenchymal stem cell origin for ALT Telomere length is maintained by 2 known mechanisms, activation of telomerase or alternative lengthening of telomeres (ALT). The molecular mechanisms regulating the ALT phenotype are poorly understood and it is unknown how the decision of which pathway to activate is made at the cellular level. We have shown previously that active repression of telomerase gene expression by chromatin remodelling of the promoters is one mechanism of regulation, however other genes and signalling networks are likely to be required to regulate telomerase and maintain the ALT phenotype. Using gene expression profiling we have uncovered a signature of 1305 genes to distinguish telomerase positive and ALT cell lines. By combining this with gene expression profiles of liposarcoma tissue samples we refined this signature to 297 genes significantly associated with telomere maintenance mechanism. Network analysis of known direct interactions between genes within this signature revealed a regulatory signalling network consistent with a model of hTERT repression in ALT cell lines and liposarcomas. This network expands on our existing knowledge of hTERT regulation and provides a platform to understand differential regulation of hTERT in different tumour types and normal tissues. In addition we show evidence to suggest a novel mesenchymal stem cell origin for ALT immortalisation in cell lines and mesenchymal tissues. Keywords: cell type comparison, gene expression
2009-11-02 | GSE14529 | GEO
Project description:Mutant template human telomerase RNAs (MT-hTers) have been shown to induce apoptosis in various cancerous cells that have high telomerase activity. However, the exact mechanisms by which MT-hTers inhibit the growth of cancer cells and affect normal somatic cells remain largely unknown. To determine the effects of MT-hTers on normal cells, MT-hTer-47A and -AU5 were introduced into IMR90 primary lung fibroblasts that have very low endogenous hTERT levels. Growth of IMR90 cells following MT-hTers infection was not impaired, however, cell proliferation of IMR90 wild-type hTERT (WT-hTERT) cells under MT-hTers-47A and -AU5 treatment was inhibited and increased cell death was observed. FACS analysis also showed that these cells underwent apoptosis. Confocal microscopy revealed that MT-hTers induced DNA damage foci, i.e., 53BP1 and ?-H2AX, in immortalized IMR90 WT-hTERT cells. Microarray analysis of the IMR90 WT-hTERT MT-hTer-47A and -AU5 versus IMR90 MT-hTer-47A and -AU5 revealed that GADD45-? was significantly elevated, and this result was further confirmed following RT-PCR and real time PCR assays. Moreover, we have showed that MT-hTers induce ATM phosphorylation at Ser 1981 in IMR90 WThTERT cells, and Western analysis revealed high levels of phospho p53 expression in these cells following activation of ATM. Our results also suggest that p53-dependent apoptosis in MT-hTers-infected IMR90 WT-hTERT cells could be due to a decreased expression of TRF2. Taken together, we propose a model that MT-hTers induce DSBs-like damages and trigger programmed cell death in IMR90 WT-hTERT cells following ATM-mediated phosphorylation of p53, which in turn upregulate GADD45-?, ultimately leading to apoptosis. MT-hTer-47A and -AU5 were introduced into IMR90 primary lung fibroblasts and immortalized IMR90 WT-hTERT cells. Through microarray analysis, gene expression of MT-hTer-infected IMR90 WT-hTERT cells were compared against MT-hTer-infected IMR90 control cells.
2011-05-28 | E-GEOD-24975 | biostudies-arrayexpress
Project description:To investigate the mechanism of telomerase regulation in BCR-ABL positive cells due to its clinical value, we studied the catalytic component of telomerase, TERT. Our results suggest that BCR-ABL plays an important role in regulating hTERT in K562 (BCR-ABL positive human leukemia) cells. When Gleevec inhibited the tyrosine kinase activity of BCR-ABL, phosphorylation of hTERT was downregulated, therefore suggesting a positive correlation between BCR-ABL and hTERT. Gleevec treatment inhibited hTERT at the mRNA level and significantly reduced telomerase activity (TA) in K562 cells, but not in HL60 or Jurkat cells. TRAP assay also revealed that Gleevec treatment significantly reduced TA specifically in K562 cells. Furthermore, translocation of hTERT from nucleoli to nucleoplasm was observed in K562 cells induced by Gleevec. Although Gleevec down-regulated hTERT mRNA level, the protein level of hTERT remained unchanged. Therefore, Gleevec-induced-TA decrease is not due to the alteration in telomerase subunits expression. It could be presumably due to posttranslational modification of hTERT, possibly through multiple signaling pathways. We have found that Gleevec reduced the tyrosine phosphorylation of hTERT by BCR-ABL, which is associated with the nucleoplasm localization of hTERT from nucleoli sequesters. These findings reveal unknown functions and regulations of telomerase by BCR-ABL.
2011-12-15 | GSE26821 | GEO
Project description:The 293T cells overexpressing human telomerase reverse transcriptase (hTERT) were lysed and co-immunoprecipitation was performed using hTERT antibody. Then protein mass spectrum was conducted in order to identify the hTERT-interacting proteins.
2024-01-26 | PXD048859 | Pride
Project description:Telomere length control is critical for cellular lifespan and tumor suppression. Telomerase is activated in the inner cell mass of the developing blastocyst to reset telomere reserves and its subsequent silencing in differentiated cells leads to gradual telomere shortening. Here, we report that transcriptional control through cis-regulatory elements minimally impact telomerase regulation as a function of pluripotency. Instead, developmental control of telomerase is largely driven by an alternative splicing event, centered around hTERT exon-2. Skipping of exon-2 triggers hTERT mRNA decay in differentiated cells. Conversely, its retention in pluripotent cells promotes telomerase accumulation. Our study also identifies SON as a regulator of exon-2 alternative splicing and we report a patient with insufficient telomerase and short telomeres and harboring a SON mutation. In summary, our study highlights a critical role for hTERT alternative splicing in the developmental regulation of telomerase and implicates defective splicing in telomere biology disorders.
2021-03-04 | GSE168193 | GEO
Project description:Although high-risk human papillomavirus (HPV) infection plays a major role in the development of cervical cancer, additive oncogenic events are involved as well. One key event involves increased activity of telomerase resulting from a deregulated expression of its catalytic subunit hTERT. Our previous microcell-mediated chromosome transfer studies revealed that introduction of human chromosome 6 in the HPV16 immortalized keratinocyte cell line FK16A and in the HPV16 containing cervical cancer cell line SiHa induced growth arrest, resulting from a repression of hTERT mRNA expression and telomerase activity. Here, this model was used to analyze expression profiles associated with hTERT deregulation in HPV transformed cells. Microarray expression analysis of 12 FK16A/chromosome 6 hybrids, four of which were negative for endogenous hTERT and 8 of which were positive for endogenous hTERT, resulted in the identification of 164 differentially expressed genes. Differential expression of a selection of 5 genes was verified by real-time RT-PCR. Of these 164 genes, 32 were also differentially expressed in other HPV transformed cells with deregulated hTERT. For 2 of these genes, encoding AQP3 and MGP, altered expression in hTERT positive cervical carcinomas was confirmed by real-time RT-PCR and immunohistochemistry, respectively. In summary we identified 32 candidate biomarkers for deregulated hTERT mRNA expression which may enable the identification of cervical premalignant lesions that are at highest risk to progress to invasive cancer. Keywords: microarray expression analysis, hTERT, cervical cancer 12 previously established cell hybrids, all carrying the same genetic background were subjected to microarray expression analysis. These hybrids were generated by the introduction of chromosome 6 in the HPV16 immortalized cell line FK16A, which resulted in a suppression of hTERT expression and telomerase activity. 8 hybrids were endogenous hTERT positive and 8 hybrids were hTERT negative. Additionally primary keratinocytes (hTERT negative), parental cell line FK16A and cervical cancer cell line SiHa (both hTERT positive) were hybridized.
2010-06-25 | E-GEOD-8288 | biostudies-arrayexpress
Project description:Although high-risk human papillomavirus (HPV) infection plays a major role in the development of cervical cancer, additive oncogenic events are involved as well. One key event involves increased activity of telomerase resulting from a deregulated expression of its catalytic subunit hTERT. Our previous microcell-mediated chromosome transfer studies revealed that introduction of human chromosome 6 in the HPV16 immortalized keratinocyte cell line FK16A and in the HPV16 containing cervical cancer cell line SiHa induced growth arrest, resulting from a repression of hTERT mRNA expression and telomerase activity. Here, this model was used to analyze expression profiles associated with hTERT deregulation in HPV transformed cells. Microarray expression analysis of 12 FK16A/chromosome 6 hybrids, four of which were negative for endogenous hTERT and 8 of which were positive for endogenous hTERT, resulted in the identification of 164 differentially expressed genes. Differential expression of a selection of 5 genes was verified by real-time RT-PCR. Of these 164 genes, 32 were also differentially expressed in other HPV transformed cells with deregulated hTERT. For 2 of these genes, encoding AQP3 and MGP, altered expression in hTERT positive cervical carcinomas was confirmed by real-time RT-PCR and immunohistochemistry, respectively. In summary we identified 32 candidate biomarkers for deregulated hTERT mRNA expression which may enable the identification of cervical premalignant lesions that are at highest risk to progress to invasive cancer. Keywords: microarray expression analysis, hTERT, cervical cancer
2008-06-25 | GSE8288 | GEO