GSK3 activates telomerase by regulating dynamic behaviour of multiple transcription factors converging on the hTERT gene
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE14532 | GEO | 2009/08/03
SECONDARY ACCESSION(S): PRJNA111611
REPOSITORIES: GEO
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Project description:Telomere elongation by telomerase is critical for the proliferation of human stem cells and >85-90% of cancer cells. The repression of telomerase activity during cellular differentiation promotes replicative aging and function as a physiological barrier for tumorigenesis in long-lived mammals, including humans. However, the underlying mechanisms remain unclear. We found that HoxC5 repressed hTERT, via a previously uncharacterized upstream enhancer element. HoxC5 interacts with co-repressors Pbx4 and Meis3, and recruits Class I histone deacetylases, to mediate repression of hTERT. The upstream enhancer element are conserved in long-lived primates, and HOXC5 are activated upon differentiation, consistent with diminished telomerase activity. Thus, HoxC5/Pbx4/Meis3 together constitute a developmental-controlled regulatory loop that coordinates transcriptional repression of hTERT.
2018-02-13 | GSE97570 | GEO
Project description:Telomerase is necessary for cell immortality in cancer. Hence, during tumerognesis cancer cells reactivates telomerase to attain uncotrolled proliferation. There are no clinically approved drugs available to inhibit telomerase in cancer. We performed a chemical screen using a novel endogenous hTERT reported cell line and identified a compound, SP2509 which acts specifically in cancer cells immortalised by WT TERT activity. Further we identified that Pirin is a molecular target of the compund and it regulate the level of SP1, an important transcriptional activator of WT TERT gene. We finally show iron dependency of pirin to activate TERT in CRC cell lines.
2022-12-01 | GSE203120 | 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: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. Using cRNA microarray, gene expression of Gleevec-treated and non-treated K562 (BCR-ABL positive) cells were compared against Gleevec-treated and non-treated HL60 (BCR-ABL deficient) cells.
2011-12-15 | E-GEOD-26821 | biostudies-arrayexpress
Project description:Human telomerase, hTERT, catalyzes telomere elongation using the hTR long noncoding RNA (lncRNA) template and confers replicative immortality, a hallmark of cancer. hTERT is reactivated in nearly 90% of cancers and telomere elongation was considered its sole role in tumorigenesis. However, evidence for telomere-independent hTERT cell phenotypes, which surprisingly require hTERT catalytic activity, is mounting. These phenotypes could profoundly impact our understanding and clinical exploitation of hTERT’s role in cancer, but their underlying mechanisms remain unclear. One mechanism was suggested by the demonstration of hTERT’s ability to bind an alternative lncRNA, RMRP, and synthesize double-stranded RNAs that are processed into Argonaute2-bound small interfering RNAs that suppress the lncRNA itself. Here we performed systematic lncRNA profiling to determine whether this is a general mode of hTERT action involving novel lncRNAs, and investigated the implications of hTERT-mediated lncRNA suppression for tumorigenesis. We found that hTERT’s telomere-independent catalytic activity increased cell survival resulting in luminal hyperplasia in a human breast acinar morphogenesis model. Using next-generation sequencing of Argonaute2-associated small RNAs, we discovered novel hTERT-downregulated lncRNAs. One such lncRNA, MEG3, could bind hTERT and was significantly downregulated in human breast carcinoma cell lines and tissues. MEG3 knockdown promoted survival and hyperplasia, consistent with early tumorigenesis, and ectopic MEG3 expression caused cell death and inhibited breast cancer cell proliferation. Microarray analysis identified Bcl2-interacting proteins, BEX1 and BNIPL, as MEG3 targets. BEX1 mediates cell death by decreasing phospho-Bcl2, and MEG3 or hTERT modulated phospho-Bcl2 levels. This pathway could, in part, underlie the observed phenotypes. Collectively, our findings show that hTERT can suppress multiple lncRNAs, including MEG3, and establish a novel mechanism of hTERT-mediated proliferative control that could facilitate tumorigenesis. Our mechanistic insights suggest that small RNA-directed diagnostic and therapeutic strategies will be relevant for targeting hTERT.
2016-09-17 | GSE61546 | 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: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