Molecular regulation of telomerase activity in aging

Nicholls, Craig; Li, He; Wang, Jian Qiu; Liu, Junping

doi:10.1007/s13238-011-1093-3

Cited by 51 publications

(39 citation statements)

References 139 publications

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“…Because transcriptional regulation of the TERT catalytic subunit is a major control mechanism for TERT expression [27] we also assessed TERT promoter activation following HCV infection in Huh-7.5 cells. TERT promoter was significantly activated early after infection and displayed a time course corresponding closely with the appearance of TERT mRNA and new protein (Fig 2D).…”

Section: Resultsmentioning

confidence: 99%

HCV Induces Telomerase Reverse Transcriptase, Increases Its Catalytic Activity, and Promotes Caspase Degradation in Infected Human Hepatocytes

et al. 2017

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IntroductionTelomerase repairs the telomeric ends of chromosomes and is active in nearly all malignant cells. Hepatitis C virus (HCV) is known to be oncogenic and potential interactions with the telomerase system require further study. We determined the effects of HCV infection on human telomerase reverse transcriptase (TERT) expression and enzyme activity in primary human hepatocytes and continuous cell lines.ResultsPrimary human hepatocytes and Huh-7.5 hepatoma cells showed early de novo TERT protein expression 2–4 days after infection and these events coincided with increased TERT promoter activation, TERT mRNA, and telomerase activity. Immunoprecipitation studies demonstrated that NS3-4A protease-helicase, in contrast to core or NS5A, specifically bound to the C-terminal region of TERT through interactions between helicase domain 2 and protease sequences. Increased telomerase activity was noted when NS3-4A was transfected into cells, when added to reconstituted mixtures of TERT and telomerase RNA, and when incubated with high molecular weight telomerase ‘holoenzyme’ complexes. The NS3-4A catalytic effect on telomerase was inhibited with primuline or danoprevir, agents that are known to inhibit NS3 helicase and protease activities respectively. In HCV infected cells, NS3-4A could be specifically recovered with telomerase holoenzyme complexes in contrast to NS5A or core protein. HCV infection also activated the effector caspase 7 which is known to target TERT. Activation coincided with the appearance of lower molecular weight carboxy-terminal fragment(s) of TERT, chiefly sized at 45 kD, which could be inhibited with pancaspase or caspase 7 inhibitors.ConclusionsHCV infection induces TERT expression and stimulates telomerase activity in addition to triggering Caspase activity that leads to increased TERT degradation. These activities suggest multiple points whereby the virus can influence neoplasia. The NS3-4A protease-helicase can directly bind to TERT, increase telomerase activity, and thus potentially influence telomere repair and host cell neoplastic behavior.

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Section: Resultsmentioning

confidence: 99%

HCV Induces Telomerase Reverse Transcriptase, Increases Its Catalytic Activity, and Promotes Caspase Degradation in Infected Human Hepatocytes

et al. 2017

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“…We observed moderate activation of telomerase activity in HeLa S3 cells with 2DG and Rsv treatment [110,112], suggesting that CR mimetic drugs have protective effects on telomeres by inducing telomerase activity along with up-regulating expression of the telomere maintenance factor-encoding genes. The human TERT (hTERT) promoter has been well characterized with c-Ets, GC-box, E-box and other TF-binding elements that are located in its 5'-flanking region [113,114]. GC-boxes and Sp1-binding sites are frequently found in the human TERT, WRN and shelterin protein-encoding gene promoters with duplicated GGAA elements that present adjacent to TSSs [110,115].…”

Section: Effect Of Caloric Restriction (Cr) Mimetic Drugs On Telomerementioning

confidence: 99%

Transcriptional Regulation of the Human Genes that Encode DNA Repair- and Mitochondrial Function-Associated Proteins

Uchiumi¹,

Larsen²,

Tanuma³

2015

Advances in DNA Repair

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“…Telomeric DNA is synthesized by telomerase, an RNA-dependent DNA polymerase [2,3]. Normal human differentiated cells exhibit a progressive telomere shortening with each cell division due to the lack of telomerase activity.…”

Section: Introductionmentioning

confidence: 99%

“…As the transcriptional activation of the TERT gene is intimately coupled with the acquisition of telomerase activity in transformed cells, the regulatory mechanism controlling the TERT transcription has been extensively investigated in recent years. However, it remains incompletely understood how the cancer-specific TERT transcription is activated [2,3]. Recently, TERT promoter mutations have been reported in human malignancies, which create de novo ETS1 binding motifs (gain of function), thereby facilitating the TERT transcription [5,6].…”

Section: Introductionmentioning

confidence: 99%

TERT promoter mutations in renal cell carcinomas and upper tract urothelial carcinomas

Wang

Liu

et al. 2014

Oncotarget

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TERT promoter mutations are identified in many malignancies including bladder cancer (BC) and upper tract urothelial carcinoma (UTUC). In contrast, no mutations were found in renal cell carcinoma (RCC) as reported in a recent study. Because the mutant TERT promoter in urine DNA was recently tested as a marker for BC, it is important to ascertain whether these mutations are truly absent in RCCs. Here we determined TERT promoter mutations in 109 patients with RCC and 14 patients with UTUC. The mutations were found in 9/96 (9.3%) clear cell RCC (ccRCC) tumors and 1/8 (13%) chromophobe RCC tumors. Among ccRCC patients, the mutation was correlated with the advanced stages and metastasis, and higher TERT expression. Among UTUCs, the mutation was detected in tumors from 3/5 (60%) patients with renal pelvic cancer and 1/9 (11%) patients with ureter cancer. The mutation was also detected in 1 of 4 urine samples from patients with mutation+ UTUC. Collectively, TERT promoter mutations do occur in RCCs and are associated with aggressive disease. The mutation is more frequent in renal pelvic cancer. Thus, the mutant TERT promoter found in urine may come from not only BC, but also RCC or UTUC.

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Molecular regulation of telomerase activity in aging

Cited by 51 publications

References 139 publications

HCV Induces Telomerase Reverse Transcriptase, Increases Its Catalytic Activity, and Promotes Caspase Degradation in Infected Human Hepatocytes

HCV Induces Telomerase Reverse Transcriptase, Increases Its Catalytic Activity, and Promotes Caspase Degradation in Infected Human Hepatocytes

Transcriptional Regulation of the Human Genes that Encode DNA Repair- and Mitochondrial Function-Associated Proteins

TERT promoter mutations in renal cell carcinomas and upper tract urothelial carcinomas

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