Oncogenesis by sequestration of CBP/p300 in transcriptionally inactive hyperacetylated chromatin domains

被引：144

作者：

Reynoird, Nicolas ^{[1
]}

Schwartz, Brian E. ^{[2
]}

Delvecchio, Manuela ^{[4
]}

Sadoul, Karin ^{[1
]}

Meyers, David ^{[3
,5
]}

Mukherjee, Chandrani ^{[3
,5
]}

Caron, Cecile ^{[1
]}

Kimura, Hiroshi ^{[6
]}

Rousseaux, Sophie ^{[1
]}

Cole, Philip A. ^{[3
,5
]}

Panne, Daniel ^{[4
]}

French, Christopher A. ^{[2
]}

Khochbin, Saadi ^{[1
]}

机构：

[1] Univ Grenoble 1, INSERM, Inst Albert Bonniot, U823, F-38700 Grenoble, France

[2] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

[3] Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA

[4] EMBL Grenoble, Grenoble, France

[5] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA

[6] Osaka Univ, Grad Sch Frontier Biosci, Suita, Osaka, Japan

来源：

EMBO JOURNAL | 2010年 / 29卷 / 17期

基金：

美国国家卫生研究院;

关键词：

Brdt; cancer testis factor; feed forward; H3K56; oncogene; BROMODOMAIN PROTEIN BRD4; HISTONE ACETYLATION; MALE GENOME; P-TEFB; P53; BINDING; FAMILY;

D O I：

10.1038/emboj.2010.176

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

In a subset of poorly differentiated and highly aggressive carcinoma, a chromosomal translocation, t(15;19)(q13;p13), results in an in-frame fusion of the double bromodomain protein, BRD4, with a testis-specific protein of unknown function, NUT (nuclear protein in testis). In this study, we show that, after binding to acetylated chromatin through BRD4 bromodomains, the NUT moiety of the fusion protein strongly interacts with and recruits p300, stimulates its catalytic activity, initiating cycles of BRD4-NUT/p300 recruitment and creating transcriptionally inactive hyperacetylated chromatin domains. Using a patient-derived cell line, we show that p300 sequestration into the BRD4-NUT foci is the principal oncogenic mechanism leading to p53 inactivation. Knockdown of BRD4-NUT released p300 and restored p53-dependent regulatory mechanisms leading to cell differentiation and apoptosis. This study demonstrates how the off-context activity of a testis-specific factor could markedly alter vital cellular functions and significantly contribute to malignant cell transformation. The EMBO Journal (2010) 29, 2943-2952. doi: 10.1038/emboj.2010.176; Published online 30 July 2010

引用

页码：2943 / 2952

页数：10

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