TERT promotes cellular and organismal survival independently of telomerase activity

Lee, J.; Sung, Young Hoon; Cheong, Cheolho; Choi, Yun Young; Jeon, Hee Kyung; Sun, Weizhong; Hahn, William C.; Ishikawa, Fuyuki; Lee, Hyun Woo

doi:10.1038/sj.onc.1211037

Cited by 122 publications

(112 citation statements)

References 48 publications

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“…TERT overexpression decreased apoptosis in PC12 cells induced by trophic factor withdrawal (Fu et al, 2000) and resulted in apparent resistance to cerebral ischemic injury and NMDA receptor-mediated neurotoxicity in the mouse brain . TERT downregulation increased the sensitivity of hippocampal neurons to excitotoxicity (Fu et al, 2000), and TERT-deficient neurons were more sensitive to NMDA than wild-type ones (Lee et al, 2008). Moreover, intrahippocampal AZT infusion caused 36.1% reduction in proliferation and 48.6% reduction in survival.…”

Section: Discussionmentioning

confidence: 98%

Hippocampal Telomerase Is Involved in the Modulation of Depressive Behaviors

Zhou¹,

Hu²,

Wu³

et al. 2011

J. Neurosci.

100

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Telomere and telomerase alterations have been reported in mood disorders. However, the role of telomerase in depression remains unclear. Here we show that chronic mild stress (CMS) led to a significant decrease in telomerase reverse transcriptase (TERT) level and telomerase activity in the hippocampus. Treatment with antidepressant fluoxetine reversed the CMS-induced TERT and telomerase activity changes. Inhibiting telomerase by systemic administration (100 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 , i.p., for 14 d), intrahippocampal microinjection (0.7 mol, 2 l), or infusion (using an osmotic minipump, 0.134 g/l, 0.25 l/h) of 3Ј-azido-deoxythymidine (AZT) resulted in depression-like behaviors and impaired hippocampal neurogenesis in mice. In contrast, overexpressing telomerase by intrahippocampal infusion of recombinant adenovirus vector expressing mouse TERT (Ad-mTERT-GFP) led to neurogenesis upregulation, produced antidepressant-like behaviors, and prevented the CMS-induced behavioral modifications. Disrupting neurogenesis in the dentate gyrus by X-irradiation (15 Gy) of a restricted region of mouse brain containing the hippocampus abolished the antidepressant-like effect of Ad-mTERT-GFP. Additionally, AZT had no effect on DNA polymerase activity and did not cause cell damage in vitro and in vivo. Microinjection of AZT into the subventricular zone of lateral ventricle (0.7 mol, 2 l) inhibited local neurogenesis but had no behavioral effect. These results suggest that hippocampal telomerase is involved in the modulation of depression-related behaviors, possibly by regulating adult neurogenesis.

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Section: Discussionmentioning

confidence: 98%

Hippocampal Telomerase Is Involved in the Modulation of Depressive Behaviors

Zhou¹,

Hu²,

Wu³

et al. 2011

J. Neurosci.

100

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“…In addition to increasing the canonical, telomere-maintenance function of hTERT, it is also possible that E6 increases hTERT protein to mediate noncanonical activities, such as apoptosis blockade (43)(44)(45), gene transcription (43,46,47), and cell proliferation (43,45,46), which could have important roles in the viral life cycle. It is very relevant that hTERT transcriptionally activates cellular gene sets that are very similar to those induced by the Wnt pathway (47) and might reflect its ability to convert primary keratinocytes into a stem-like state (mentioned above).…”

Section: Discussionmentioning

confidence: 99%

HPV E6 protein interacts physically and functionally with the cellular telomerase complex

Liu

Dakić

Zhang

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

116

101

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Telomerase activation is critical for the immortalization of primary human keratinocytes by the high-risk HPV E6 and E7 oncoproteins, and this activation is mediated in part by E6-induction of the hTERT promoter. E6 induces the hTERT promoter via interactions with the cellular ubiquitin ligase, E6AP, and with the c-Myc and NFX-1 proteins, which are resident on the promoter. In the current study we demonstrate that E6 protein interacts directly with the hTERT protein. Correlating with its ability to bind hTERT, E6 also associates with telomeric DNA and with endogenous active telomerase complexes. Most importantly, E6 increases the telomerase activity of human foreskin fibroblasts transduced with the hTERT gene, and this activity is independent of hTERT mRNA expression. Unlike its ability to degrade p53, E6 does not degrade hTERT protein in vitro or in vivo. Our studies of E6/hTERT interactions also reveal that the C-terminal tagged hTERT protein, although incapable of immortalizing fibroblasts, does immortalize keratinocytes in collaboration with the viral E7 protein. Thus, E6 protein mediates telomerase activation by a posttranscriptional mechanism and these findings provide a model for exploring the direct modulation of cell telomerase/telomere function by an oncogenic virus and suggest its potential role in both neoplasia and virus replication.cell immortalization ͉ hTERT ͉ oncoproteins ͉ papillomavirus T he HPV-16 E6 oncoprotein increases cellular telomerase activity, predominantly by inducing transcription of the hTERT gene (1-6). The hTERT protein is the catalytic, ratelimiting subunit of the telomerase enzyme complex and is selectively expressed in a small subset of normal cells (stem cells), tumor tissues, and tumor-derived cell lines (7-10). Interestingly, overexpression of hTERT or c-Myc (which transactivates the hTERT promoter) can substitute for E6 in the immortalization of primary HFKs, indicating that telomerase activation constitutes a major immortalizing function of E6 (11,12). Our previous studies and those of other laboratories indicate that E6-mediated hTERT transactivation is independent of its ability to degrade p53 or interact with PDZ proteins (11-16). However, hTERT transactivation by E6 is dependent upon its binding the cellular ubiquitin ligase, E6AP (13,14,(17)(18)(19)(20). There appear to be two critical targets for E6/E6AP on the hTERT promoter, Myc (12, 15, 16) and NFX-1 (13, 18, 21), which transactivate and transrepress the promoter respectively. The model for E6 regulation of the hTERT promoter is likely to be quite complex and it is anticipated that there might be additional targets for E6 on this promoter.In addition to activating telomerase, E6 interacts with a spectrum of cellular proteins that may contribute to HPV oncogenicity. For example, E6 binds proteins that regulate cell differentiation, adhesion, polarity, proliferation, apoptosis, gene transcription, and chromosomal stability (22,23). E6 interacts with these target proteins via several mechanisms, including two known ...

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“…In this report, Lee et al have demonstrated by using both cell cultures and a transgenic mouse model that expression of TERT was directly associated with increased resistance to apoptosis induced by staurosporine (STS) or N-methyl-D-aspartic acid (NMDA) treatment. Importantly, these investigators have shown that the antiapoptotic effect of TERT was independent of telomere maintenance and telomerase activity [34].…”

Section: Telomerase In Apoptosismentioning

confidence: 99%

“…Recent studies showed that down-regulation of hTERT expression by hTERT specific interfering RNA (siRNA) sensitizes mitochondrial pathways of apoptosis without apparent involvement of telomere erosion due to telomerase inhibition, rather by post-translational activation of Bax protein which triggers a CD-90 independent mitochondrial pathway of apoptosis [33]. More recent report indicated that TERT promotes cellular and organismal survival independent of telomerase activity [34]. In this report, Lee et al have demonstrated by using both cell cultures and a transgenic mouse model that expression of TERT was directly associated with increased resistance to apoptosis induced by staurosporine (STS) or N-methyl-D-aspartic acid (NMDA) treatment.…”

Section: Telomerase In Apoptosismentioning

confidence: 99%