E6 oncoprotein represses p53-dependent gene activation via inhibition of protein acetylation independently of inducing p53 degradation

Mary C. Thomas, Cheng Ming Chiang

Research output: Contribution to journalArticle

154 Citations (Scopus)

Abstract

The mechanism employed by DNA tumor viruses to inhibit p53-dependent transcription from chromatin is poorly understood. Here, we use in vitro-reconstituted chromatin and UV-irradiated cells to define the mechanism of human papillomavirus E6 oncoprotein in repressing p53-dependent transcription. We demonstrate that E6 does not prevent p53 or p300 recruitment to the chromatin but inhibits p300-mediated acetylation on p53 and nucleosomal core histones. This suppression of protein acetylation requires the E6-interacting regions of p300. Moreover, E6 mutants unable to interact with p53 or p300, but not deficient in inducing p53 degradation, fail to inhibit p53-mediated activation, indicating that a p53-E6-p300-containing protein complex is critical for repressing p53-targeted gene activation. That E6 acts as a molecular switch converting p53-p300 from an activating complex to a repressing entity on the chromatin, which occurs independently of E6AP-mediated protein degradation pathway, may represent a general mechanism for gene regulation.

Original languageEnglish (US)
Pages (from-to)251-264
Number of pages14
JournalMolecular Cell
Volume17
Issue number2
DOIs
StatePublished - Jan 21 2005

Fingerprint

Tumor Suppressor Protein p53
p53 Genes
Acetylation
Transcriptional Activation
Chromatin
Proteins
DNA Tumor Viruses
Oncogene Proteins
Histones
Proteolysis
Genes

ASJC Scopus subject areas

  • Molecular Biology

Cite this

E6 oncoprotein represses p53-dependent gene activation via inhibition of protein acetylation independently of inducing p53 degradation. / Thomas, Mary C.; Chiang, Cheng Ming.

In: Molecular Cell, Vol. 17, No. 2, 21.01.2005, p. 251-264.

Research output: Contribution to journalArticle

@article{9c3ffaf882d24c0bbb0a746a98229259,
title = "E6 oncoprotein represses p53-dependent gene activation via inhibition of protein acetylation independently of inducing p53 degradation",
abstract = "The mechanism employed by DNA tumor viruses to inhibit p53-dependent transcription from chromatin is poorly understood. Here, we use in vitro-reconstituted chromatin and UV-irradiated cells to define the mechanism of human papillomavirus E6 oncoprotein in repressing p53-dependent transcription. We demonstrate that E6 does not prevent p53 or p300 recruitment to the chromatin but inhibits p300-mediated acetylation on p53 and nucleosomal core histones. This suppression of protein acetylation requires the E6-interacting regions of p300. Moreover, E6 mutants unable to interact with p53 or p300, but not deficient in inducing p53 degradation, fail to inhibit p53-mediated activation, indicating that a p53-E6-p300-containing protein complex is critical for repressing p53-targeted gene activation. That E6 acts as a molecular switch converting p53-p300 from an activating complex to a repressing entity on the chromatin, which occurs independently of E6AP-mediated protein degradation pathway, may represent a general mechanism for gene regulation.",
author = "Thomas, {Mary C.} and Chiang, {Cheng Ming}",
year = "2005",
month = "1",
day = "21",
doi = "10.1016/j.molcel.2004.12.016",
language = "English (US)",
volume = "17",
pages = "251--264",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "2",

}

TY - JOUR

T1 - E6 oncoprotein represses p53-dependent gene activation via inhibition of protein acetylation independently of inducing p53 degradation

AU - Thomas, Mary C.

AU - Chiang, Cheng Ming

PY - 2005/1/21

Y1 - 2005/1/21

N2 - The mechanism employed by DNA tumor viruses to inhibit p53-dependent transcription from chromatin is poorly understood. Here, we use in vitro-reconstituted chromatin and UV-irradiated cells to define the mechanism of human papillomavirus E6 oncoprotein in repressing p53-dependent transcription. We demonstrate that E6 does not prevent p53 or p300 recruitment to the chromatin but inhibits p300-mediated acetylation on p53 and nucleosomal core histones. This suppression of protein acetylation requires the E6-interacting regions of p300. Moreover, E6 mutants unable to interact with p53 or p300, but not deficient in inducing p53 degradation, fail to inhibit p53-mediated activation, indicating that a p53-E6-p300-containing protein complex is critical for repressing p53-targeted gene activation. That E6 acts as a molecular switch converting p53-p300 from an activating complex to a repressing entity on the chromatin, which occurs independently of E6AP-mediated protein degradation pathway, may represent a general mechanism for gene regulation.

AB - The mechanism employed by DNA tumor viruses to inhibit p53-dependent transcription from chromatin is poorly understood. Here, we use in vitro-reconstituted chromatin and UV-irradiated cells to define the mechanism of human papillomavirus E6 oncoprotein in repressing p53-dependent transcription. We demonstrate that E6 does not prevent p53 or p300 recruitment to the chromatin but inhibits p300-mediated acetylation on p53 and nucleosomal core histones. This suppression of protein acetylation requires the E6-interacting regions of p300. Moreover, E6 mutants unable to interact with p53 or p300, but not deficient in inducing p53 degradation, fail to inhibit p53-mediated activation, indicating that a p53-E6-p300-containing protein complex is critical for repressing p53-targeted gene activation. That E6 acts as a molecular switch converting p53-p300 from an activating complex to a repressing entity on the chromatin, which occurs independently of E6AP-mediated protein degradation pathway, may represent a general mechanism for gene regulation.

UR - http://www.scopus.com/inward/record.url?scp=12344295621&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=12344295621&partnerID=8YFLogxK

U2 - 10.1016/j.molcel.2004.12.016

DO - 10.1016/j.molcel.2004.12.016

M3 - Article

C2 - 15664194

AN - SCOPUS:12344295621

VL - 17

SP - 251

EP - 264

JO - Molecular Cell

JF - Molecular Cell

SN - 1097-2765

IS - 2

ER -