Destabilization of TIP60 by Human Papillomavirus E6 Results in Attenuation of TIP60-Dependent Transcriptional Regulation and Apoptotic Pathway

Jha, Sudhakar; Pol, Scott Vande; Banerjee, N. Sanjib; Dutta, Arun B.; Chow, Louise T.; Dutta, Anindya

doi:10.1016/j.molcel.2010.05.020

Cited by 116 publications

(153 citation statements)

References 61 publications

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“…K120 acetylation is crucial for p53-mediated apoptosis but has no obvious effect on p21 expression, an essential target of p53-mediated growth arrest. Notably, although Tip60 is required for K120 acetylation of p53 in vivo, the levels of K120 acetylation are dynamically regulated in vivo and the interaction between p53 and Tip60 is not very stable, indicating that additional regulators may play a role in controlling K120 acetylation and subsequent p53-mediated apoptotic response (18)(19)(20). Through biochemical purification, we identified p90 as a unique regulator for p53.…”

mentioning

confidence: 97%

Differential effects on p53-mediated cell cycle arrest vs. apoptosis by p90

Dai

Tang

Jung

et al. 2011

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

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p53 functions as a central node for organizing whether the cell responds to stress with apoptosis or cell cycle arrest; however, the molecular events that lead to apoptotic responses are not completely understood. Here, we identified p90 (also called Coiled-Coil Domain Containing 8) as a unique regulator for p53. p90 has no obvious effects on either the levels of p53 or p53-mediated cell cycle arrest but is specifically required for p53-mediated apoptosis upon DNA damage. Notably, p90 is crucial for Tip60-dependent p53 acetylation at Lys120, therefore facilitating activation of the proapoptotic targets. These studies indicate that p90 is a critical cofactor for p53-mediated apoptosis through promoting Tip60-mediated p53 acetylation.T he p53 tumor suppressor acts as the major sensor for a regulatory circuit that monitors signaling pathways from diverse sources, including DNA damage, oncogenic events, and other abnormal cellular processes (1, 2). p53 monitors and responds to a multitude of stress signals by coordinating cell growth arrest or apoptosis (3-5). Central to p53 regulation of these cellular processes is its activity as a transcription factor, although transcription-independent functions of p53 are also critical under some biological settings. The activation of p53 transcription activity requires multiple steps, including sequence-specific DNA binding, antirepression and acquirement of combinations of posttranslational modifications, and recruitment of corepressors/coactivators in a promoter-specific manner (6). To suppress tumor growth, p53 induces either cell growth arrest or apoptosis depending on the cellular context. The molecular mechanisms that govern the choice between growth arrest and apoptosis are extremely important but not well understood (4, 7). As a key player in the stress response, p53 demands an exquisitely complicated network of control and fine-tuning mechanisms to ensure correct, differentiated responses to the various stress signals encountered by cells (2,5,(8)(9)(10).p53 was the first nonhistone protein known to be regulated by acetylation and deacetylation (11,12). There is accumulating evidence indicating that acetylation of p53 plays a major role in activating p53 function during stress responses (2, 13, 14). Following our early findings of C terminus p53 acetylation, we and others recently showed that p53 is also acetylated by Tip60 (also known as KAT5)/MOF (human ortholog of males absent on the first) at residue Lys120 (K120) within the DNA-binding domain (15-17). K120 acetylation is crucial for p53-mediated apoptosis but has no obvious effect on p21 expression, an essential target of p53-mediated growth arrest. Notably, although Tip60 is required for K120 acetylation of p53 in vivo, the levels of K120 acetylation are dynamically regulated in vivo and the interaction between p53 and Tip60 is not very stable, indicating that additional regulators may play a role in controlling K120 acetylation and subsequent p53-mediated apoptotic response (18)(19)(20). Through biochemical pur...

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mentioning

confidence: 97%

Differential effects on p53-mediated cell cycle arrest vs. apoptosis by p90

Dai

Tang

Jung

et al. 2011

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

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“…At this juncture, our search for other probable acetyl transferases revealed an increment in the endogenous tumor suppressor acetyl transferase Tip60 protein expression in the HPV18-infected cervical carcinoma cells under curcumin-treated conditions. It has been reported that whereas Tip60 promotes the proapoptotic Lys-120 acetylation of p53, thereby executing its anti-tumor function (14), it is degraded by the proto-oncogene E6 in the cervical adenocarcinoma cells (15). In our experimental sets, curcumin-induced repression of E6 via SMAR1 rescues Tip60 from E6-mediated degradation and promotes acetylation and activation of p53 to initiate downstream apoptotic pathways.…”

Section: Discussionmentioning

confidence: 59%

“…(38, 39). However, Tip60 has been shown to be down-regulated in HPV18-infected cervical adenocarcinoma cells in which HPV 18 E6 degrades it in a proteosome-dependent pathway (15). Our results depicted a significant restoration and increase in Tip60 expression in HeLa cells after curcumin treatment in a time-dependent manner (Fig.…”

Section: Inhibition Of E6 Reinstalls Apoptotic Program In Hpv18-infecmentioning

confidence: 50%

“…Tumor suppressor p53, being stabilized by SMAR1 and acetylated by Tip60, in turn induces SMAR1 to orchestrate the cycle that leads to HPV18-infected cervical adenocarcinoma cell apoptosis via p53-mediated transactivation of proapoptotic genes. In fact, earlier reports have shown that Tip60 also promotes repression of E6 after it was rescued from E6-mediated degradation (15). Cumulatively, restoration of SMAR1 by curcumin effectively warrants apoptosis in cervical cancer cells.…”

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confidence: 92%

“…In this relation, acetylation of histone, as well as other transcription regulatory non-histone factors by lysine acetyltransferases, e.g. Tip60 (14,15), commonly correlates with the open chromatin structures required for the binding of multiple transcription factors and leads to transcriptional activation correlated with an increase in gene expression, whereas removal of acetyl groups by histone deacetylases (HDACs) accompanies with transcriptional repression. Lysine acetyltransferases and HDACs have been shown to play a critical role in transcriptional regulation in eukaryotic cells.…”

mentioning

confidence: 99%

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Nuclear Matrix Protein SMAR1 Represses c-Fos-mediated HPV18 E6 Transcription through Alteration of Chromatin Histone Deacetylation

Chakraborty

Das

Saha

et al. 2014

Journal of Biological Chemistry

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Background: HPV18 E6 oncogene represents one of the most promising therapeutic targets for the treatment of HPVpositive tumors. Results: Curcumin-induced SMAR1-HDAC1 recruitment at LCR and E6 region on E6 promoter deacetylates chromatin histones to attenuate c-Fos-mediated E6 transcription to reinstall p53-mediated apoptosis in HPV18-infected cervical cancer. Conclusion: SMAR1 induces E6 repression. Significance: SMAR1 is a repressor of E6-mediated anti-apoptotic network in HPV18-infected cervical cancers.

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Skin Cancer in the Immunocompromised Patient

Harwood

McGregor

Proby³

2016

Rook's Textbook of Dermatology, Ninth Edition

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The immune system plays a critical role in skin cancer development, progression and destruction. Skin cancers in individuals with compromised immune systems represent a growing challenge in terms of their frequency and diversity as well as their atypical and often aggressive nature. Mortality and morbidity associated with skin tumours in this clinical context are often considerable, their pathogenesis is multifactorial and an evidence base to guide management is lacking in many key areas.

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Destabilization of TIP60 by Human Papillomavirus E6 Results in Attenuation of TIP60-Dependent Transcriptional Regulation and Apoptotic Pathway

Cited by 116 publications

References 61 publications

Differential effects on p53-mediated cell cycle arrest vs. apoptosis by p90

Differential effects on p53-mediated cell cycle arrest vs. apoptosis by p90

Nuclear Matrix Protein SMAR1 Represses c-Fos-mediated HPV18 E6 Transcription through Alteration of Chromatin Histone Deacetylation

Skin Cancer in the Immunocompromised Patient

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