Telomerase activation by the E6 gene product of human papillomavirus type 16

Klingelhutz, Aloysius J.; Foster, Scott A.; McDougall, James K.

doi:10.1038/380079a0

Cited by 729 publications

(552 citation statements)

References 20 publications

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“…HPV 16 E6 has multiple activities and at least two appear to be relevant for immortalization: inactivation of the p53 protein (Liu et al, 1999b) and induction of telomerase (Klingelhutz et al, 1996). Interestingly, a subset of immortalizing E6 mutants that do not degrade p53 still target the hAda3 protein for degradation and inhibit p53-mediated transactivation (Kumar et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

hAda3 regulates p14ARF-induced p53 acetylation and senescence

et al. 2007

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Acetylation is thought to be a key event for p53 activation. We demonstrate that p14ARF-induced senescence of human mammary epithelial cells (MEC) is associated with p53 acetylation and requires hAda3, a component of histone acetyltransferase complexes and a p53 transcriptional coactivator. Expression of the N-terminal domain of hAda3 that binds p53 but not p300 blocked p14ARF-induced p53 acetylation and protected MECs from senescence. Consistent with these findings, the human papillomavirus 16 E6 mutant Y54D, which selectively targets hAda3 but not p53 for degradation and protects MECs from p14ARF-induced senescence, inhibited p53 acetylation. In H1299 cells, hAda3 overexpression increased p300-mediated p53 acetylation, which conversely decreased following small interfering RNA (siRNA) knockdown of hAda3. Moreover, depletion of hAda3 by siRNA inhibited endogenous p53 acetylation and accumulation of p21cip1 in response to ectopic p14ARF. These studies reveal that, in addition to its known ability to inhibit Mdm2-mediated p53 degradation, p14ARF signals through hAda3 to stimulate p53 acetylation and the induction of cell senescence.

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Section: Introductionmentioning

confidence: 99%

hAda3 regulates p14ARF-induced p53 acetylation and senescence

et al. 2007

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“…In addition, at least some E6 activities, such as activation of telomerase, appear to be cell-type dependent (Klingelhutz et al, 1996). These observations indicate that it is difficult to deduce the critical activities of E6 in HPV-positive cancer cells from the various effects observed after ectopic (over)expression of E6, in heterologous cell systems.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Bax activity is crucial for the antiapoptotic function of the human papillomavirus E6 oncoprotein

et al. 2006

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Oncogenic types of human papillomaviruses (HPVs) cause cervical cancer in humans. The antiapoptotic viral E6 gene has been identified as a key factor for maintaining the viability of HPV-positive cancer cells. Although E6 has the potential to modulate many apoptosis regulators, the crucial apoptotic pathway blocked by endogenous E6 in cervical cancer cells remained unknown. Using RNA interference (RNAi), here, we show that targeted inhibition of E6 expression in cervical cancer cells leads to the transcriptional stimulation of the PUMA promoter, in a p53-dependent manner. This is linked to the activation and translocation of Bax to the mitochondrial membrane, cytochrome c release into the cytosol, and activation of caspase-3, in a PUMA-dependent manner. Moreover, inhibition of Bax expression by RNAi efficiently reverts the apoptotic phenotype, which results from inhibition of E6 expression. Thus, interference with the p53/PUMA/ Bax cascade is crucial for the antiapoptotic function of the viral E6 oncogene in HPV-positive cancer cells.

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“…The de novo transcription of the hTERT gene is considered the dominant, rate-limiting step in telomerase activation whereas the expression of hTEP1 and hTR is constitutive [1,9]. The regulation of hTERT expression is complicated, and it has been reported that hTERT transcription can be activated by overexpression or activation of several transcription activators [8,17,20,24,33,36]. Several recent reports have identified c-myc binding sites (E-boxes) in the hTERT promoter and found that c-myc positively regulates hTERT expression [11,30].…”

Section: Introductionmentioning

confidence: 99%

Effects of histone deacetylase inhibitor FR901228 on the expression level of telomerase reverse transcriptase in oral cancer

Murakami

Asaumi

Kawai

et al. 2005

Cancer Chemother Pharmacol

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We speculated whether or not the expression level of telomerase reverse transcriptase (hTERT) would be modulated by agents targeting epigenetics in oral cancer cell lines. Although hTERT is known to be targeted by epigenetic changes, it remains unclear how chemoagents targeting epigenetics work on hTERT transcription. In the present study, the epigenetic effects of histone deacetylase (HDAC) inhibitor FR901228 on hTERT transcription were analysed by RT-PCR in oral cancer cell lines. The mRNA expression of hTERT was upregulated after exposure to FR901228 in hTERT-negative Hep2 cells, even in the hTERT highly expressed SAS and KB cells.Moreover, co-treatment of protein synthesis inhibitor cycloheximide (CHX) resulted in the induction of hTERT transcription by FR901228. This suggests that the induction of hTERT by FR901228 requires de novo protein synthesis to some extent and is more likely a direct than an indirect effect on epigenetic changes such as histone acetylation / deacetylation. We further examined the effect of FR901228 on c-myc protein, which is one of the main hTERT transcription activators. FR901228 repressed c-myc protein only in the absence of CHX, dependent of the enhancement of de novo protein synthesis. Our results indicate that c-myc protein is repressed indirectly by FR901228 but may not contribute FR901228-induced hTERT transcription. The present study showed that the HDAC inhibitor FR901228 induced the hTERT gene by a complex mechanism that involved other transcription factors except for c-myc, in addition to the inhibition of histone deacetylation.

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Telomerase activation by the E6 gene product of human papillomavirus type 16

Cited by 729 publications

References 20 publications

hAda3 regulates p14ARF-induced p53 acetylation and senescence

hAda3 regulates p14ARF-induced p53 acetylation and senescence

Inhibition of Bax activity is crucial for the antiapoptotic function of the human papillomavirus E6 oncoprotein

Effects of histone deacetylase inhibitor FR901228 on the expression level of telomerase reverse transcriptase in oral cancer

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