The E6 protein of human papillomavirus type 16 binds to and inhibits co-activation by CBP and p300

Patel, Daksha; Huang, Shih-Min A.; Baglia, Laurel A.; McCance, Dennis J.

doi:10.1093/emboj/18.18.5061

Cited by 383 publications

(386 citation statements)

References 63 publications

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“…Using a different approach, it was reported that HPV18 E6 blocked p53 acetylation independent of its degradation (Thomas and Chiang, 2005). E6 inhibition of p300 has been described (Patel et al, 1999;Zimmermann et al, 1999). We propose that E6 targets hAda3, thereby blocking p300-mediated acetylation and activation of p53 and preventing cell senescence.…”

Section: Discussionmentioning

confidence: 90%

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: Discussionmentioning

confidence: 90%

hAda3 regulates p14ARF-induced p53 acetylation and senescence

et al. 2007

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“…Apart from methylation changes in this virus genome, other epigenetic changes might occur through direct interactions between HPV proteins (E2, E7) and cell proteins involved in DNA methylation (DNMT1) (Burgers et al, 2006), or through processes related to the chromatin remodeling machinery (CBP, pCAF, p300, Mi2b) (Brehm et al, 1999;Patel et al, 1999;Lee et al, 2000;Peng et al, 2000;Avvakumov et al, 2003;Bernat et al, 2003), eventually modifying the normal epigenetic processes in the host.…”

Section: Human Papilloma Virusmentioning

confidence: 99%

Viral epigenomes in human tumorigenesis

Fernández

Esteller

2010

Oncogene

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Viruses are associated with 15-20% of human cancers worldwide. In the last century, many studies were directed towards elucidating the molecular mechanisms and genetic alterations by which viruses cause cancer. The importance of epigenetics in the regulation of gene expression has prompted the investigation of virus and host interactions not only at the genetic level but also at the epigenetic level. In this study, we summarize the published epigenetic information relating to the genomes of viruses directly or indirectly associated with the establishment of tumorigenic processes. We also review aspects such as viral replication and latency associated with epigenetic changes and summarize what is known about epigenetic alterations in host genomes and the implications of these for the tumoral process. The advances made in characterizing epigenetic features in cancer-causing viruses have improved our understanding of their functional mechanisms. Knowledge of the epigenetic changes that occur in the genome of these viruses should provide us with markers for following cancer progression, as well as new tools for cancer therapy.

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“…Other hypotheses have been raised to explain how E6 inactivates p53 independently of E6AP, specifically, through E6's binding to the p53 transcriptional coactivators p300/CBP (Patel et al, 1999;Thomas and Chiang, 2005) or ADA3 , thereby blocking p53-dependent transcription. It is difficult, however, to reconcile our results with these alternative hypotheses, as we observed a continued ability of E6 to inhibit the induction of p53 on the E6AP-deficient/ defective backgrounds, an observation that is not predicted by these alternative hypotheses.…”

Section: E6ap Is Not Required For E6's Inactivation Of Mouse P53mentioning

confidence: 99%

HPV16 E6 confers p53-dependent and p53-independent phenotypes in the epidermis of mice deficient for E6AP

Shai

Wagstaff

et al. 2006

Oncogene

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High-risk human papillomaviruses are the causative agents of cervical and other anogenital cancers. In these cancers, two viral oncogenes, E6 and E7, are expressed. E6 is best known for its ability to inactivate the tumor suppressor p53, which is thought to arise through ubiquitin-mediated degradation of p53 and involve a ternary complex between E6, p53 and the E3 ligase, E6AP. In mice transgenic for wild-type HPV16 E6, its expression leads to epithelial hyperplasia and an abrogation of normal cellular responses to DNA damage. Whereas only the latter phenotype is dependent upon E6's inactivation of p53, both are reduced in transgenic mice expressing an E6 mutant severely reduced in its binding to E6AP and other cellular proteins that bind E6 through a shared a-helix motif. Here, we investigated whether E6AP is required for the induction of the above phenotypes through the use of both E6AP-mutant and E6AP-null mice. E6, in the absence of E6AP retains an ability to induce epithelial hyperplasia, abrogate DNA damage responses and inhibit the induction of p53 protein following exposure to ionizing radiation. We conclude that E6 is able to induce both p53-dependent and p53-independent phenotypes through E6AP-independent pathways in the mouse.

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The E6 protein of human papillomavirus type 16 binds to and inhibits co-activation by CBP and p300

Cited by 383 publications

References 63 publications

hAda3 regulates p14ARF-induced p53 acetylation and senescence

hAda3 regulates p14ARF-induced p53 acetylation and senescence

Viral epigenomes in human tumorigenesis

HPV16 E6 confers p53-dependent and p53-independent phenotypes in the epidermis of mice deficient for E6AP

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