Hypoxia Up-Regulates Telomerase Activity via Mitogen-Activated Protein Kinase Signaling in Human Solid Tumor Cells

Seimiya, Hiroyuki; Tanji, Masanori; Oh‐hara, Tomoko; Tomida, Akihiro; Naasani, Imad; Tsuruo, Takashi

doi:10.1006/bbrc.1999.0910

Cited by 85 publications

(70 citation statements)

References 39 publications

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“…These findings suggest the existence of mechanisms by which tumor cells can protect their chromosome structure from hypoxia-induced genotoxicity. Consistent with this concept, previous studies have demonstrated that telomerase is activated under hypoxic conditions (Seimiya et al, 1999;Minamino et al, 2001), suggesting that telomerase activation is a mechanism that protects against genetic stress induced by hypoxia. However, the molecular mechanisms by which hypoxia activates telomerase are not fully understood.…”

Section: Introductionsupporting

confidence: 59%

HIF-1-mediated activation of telomerase in cervical cancer cells

et al. 2004

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Hypoxia-inducible factor 1 (HIF-1) is a key regulator of O 2 homeostasis, which regulates the expression of several genes linked to angiogenesis and energy metabolism. Tumor hypoxia has been shown to be associated with poor prognosis in a variety of tumors, and HIF-1 induced by hypoxia plays pivotal roles in tumor progression. The presence of putative HIF-1-binding sites on the promoter of human telomerase reverse transcriptase gene (hTERT) prompted us to examine the involvement of HIF-1 in the regulation of hTERT and telomerase in tumor hypoxia. The telomeric repeat amplification protocol (TRAP) assay revealed that hypoxia activated telomerase in cervical cancer ME180 cells, with peak induction at 24-48 h of hypoxia. Notably, hTERT mRNA expression was upregulated at 6-12 h of hypoxia, concordant with the elevation of HIF-1 protein levels at 6 h. hTERT protein levels were subsequently upregulated at 24 h and later. Luciferase assays using reporter plasmids containing hTERT core promoter revealed that hTERT transcription was significantly activated in hypoxia and by HIF-1 overexpression, and that the two putative binding sites within the core promoter are responsible for this activation. Chromatin immunoprecipitation assay identified the specific binding of HIF-1 to these sites (competing with c-Myc), which was enhanced in hypoxia. The present findings suggest that hypoxia activates telomerase via transcriptional activation of hTERT, and that HIF-1 plays a critical role as a transcription factor. They also suggest the existence of novel mechanisms of telomerase activation in cancers, and have implications for the molecular basis of hypoxia-induced tumor progression and HIF-1-based cancer gene therapy.

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Section: Introductionsupporting

confidence: 59%

HIF-1-mediated activation of telomerase in cervical cancer cells

et al. 2004

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“…Hypoxic conditions were achieved using an anaerobic chamber and BBL GasPac Plus (Becton Dickinson, Cockeysville, MD, USA), which catalytically reduces oxygen levels to less than 10 p.p.m. within 90 min (Seimiya et al, 1999). To achieve low serum conditions, we cultured cells in the medium containing 0.1% fetal bovine serum.…”

Section: Methodsmentioning

confidence: 99%

Promotion of glioma cell survival by acyl-CoA synthetase 5 under extracellular acidosis conditions

Mashima

Sato²,

Sugimoto

et al. 2008

Oncogene

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Extracellular acidosis (low pH) is a tumor microenvironmental stressor that has a critical function in the malignant progression and metastatic dissemination of tumors. To survive under stress conditions, tumor cells must evolve resistance to stress-induced toxicity. AcylCoA synthetase 5 (ACSL5) is a member of the ACS family, which converts fatty acid to acyl-CoA. ACSL5 is frequently overexpressed in malignant glioma, whereas its functional significance is still unknown. Using retrovirusmediated stable gene transfer (gain of function) and small interfering RNA-mediated gene silencing (loss of function), we show here that ACSL5 selectively promotes human glioma cell survival under extracellular acidosis. ACSL5 enhanced cell survival through its ACS catalytic activity. To clarify the genome-wide changes in cell signaling pathways by ACSL5, we performed cDNA microarray analysis and identified an ACSL5-dependent gene expression signature. The analysis revealed that ACSL5 was critical to the expression of tumor-related factors including midkine (MDK), a heparin-binding growth factor frequently overexpressed in cancer. Knockdown of MDK expression significantly attenuated ACSL5-mediated survival under acidic state. These results indicate that ACSL5 is a critical factor for survival of glioma cells under acidic tumor microenvironment, thus providing novel molecular basis for cancer therapy.

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“…In addition to their effect at transcriptional levels, hypoxia or HIF-1a is capable of enhancing telomerase activity via other pathways (10)(11)(12)(13)(14). Alternatively spliced hTERT mRNA contributes to telomerase regulation under certain settings, and it has been established that the full-length hTERT transcripts, rather than any other variants, is translated into a functional protein required for active telomerase (5,6,(24)(25)(26)(27)(28)(29)(30).…”

Section: Discussionmentioning

confidence: 99%

“…By promoting angiogenesis, HIF-1 plays important roles in progression, invasiveness, or metastasis of malignant diseases (7,8). Furthermore, recent studies have suggested that hypoxic treatment or overexpression of HIF-1a affects hTERT and telomerase expression (10)(11)(12)(13)(14)(15)(16). Most observations showed that the incubation of human cancer cells at lower levels of oxygen enhanced hTERT mRNA expression and telomerase activity via HIF-1a -mediated trans-activation of the hTERT gene.…”

Section: Introductionmentioning

confidence: 99%

“…(a) Koshiji et al observed that hypoxia-induced HIF-1a significantly inhibited hTERT expression in human colon cancer cells, in sharp contrast to other reports (11). (b) Different mechanisms, including transcriptional and post-transcriptional approaches, have been implicated in hypoxia-regulated hTERT expression (10,(12)(13)(14)16). It remains to be defined whether these regulatory pathways contribute to the enhanced hTERT expression or telomerase activity in all human cancer cells.…”

Section: Introductionmentioning

confidence: 99%

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The Opposing Effect of Hypoxia-Inducible Factor-2α on Expression of Telomerase Reverse Transcriptase

Lou¹,

Chen

Jalink

et al. 2007

Molecular Cancer Research

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Hypoxia-inducible factor-1A (HIF-1A) has been implicated in the transcriptional regulation of the telomerase reverse transcriptase (hTERT) gene expression and telomerase activity, essential elements for cellular immortalization and transformation. However, controversial results were obtained in different studies. Moreover, it is totally unclear whether HIF-2A, the paralog of HIF-1A, plays a role in regulating hTERT expression. In the present study, we found that hypoxic treatment enhanced hTERT mRNA expression and telomerase activity in three renal cell carcinoma (RCC) cell lines with different genetic backgrounds. Both HIF-1A and HIF-2A were capable of significantly increasing the hTERT promoter activity in these cells. Moreover, depleting HIF-2A led to a down-regulation of hTERT mRNA level in RCC A498 cells expressing constitutive HIF-2A. It was found that HIF-2A bound to the hTERT proximal promoter and enhanced the recruitment of the histone acetyltransferase p300 and histone H3 acetylation locally in A498 cells treated with hypoxia. Increased levels of hTERT mRNA were observed in two of three hypoxia-treated malignant glioma cell lines. However, HIF-1A stimulated whereas HIF-2A inhibited the hTERT promoter activity in these glioma cell lines. Ectopic expression of HIF-2A resulted in diminished hTERT expression in glioma cells. Collectively, HIF-1A activates hTERT and telomerase expression in both RCC and glioma cells, and HIF-2A enhances hTERT expression in RCC cells, whereas it represses the hTERT transcription in glioma cells.

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Hypoxia Up-Regulates Telomerase Activity via Mitogen-Activated Protein Kinase Signaling in Human Solid Tumor Cells

Cited by 85 publications

References 39 publications

HIF-1-mediated activation of telomerase in cervical cancer cells

HIF-1-mediated activation of telomerase in cervical cancer cells

Promotion of glioma cell survival by acyl-CoA synthetase 5 under extracellular acidosis conditions

The Opposing Effect of Hypoxia-Inducible Factor-2α on Expression of Telomerase Reverse Transcriptase

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