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p53 is regulated by the lysine demethylase LSD1
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作者:

Huang, Jing
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机构: Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA

Sengupta, Roopsha
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机构: Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA

Espejo, Alexsandra B.
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机构: Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA

Lee, Min Gyu
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机构: Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA

Dorsey, Jean A.
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机构: Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA

Richter, Mario
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机构: Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA

Opravil, Susanne
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机构: Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA

Shiekhattar, Ramin
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机构: Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA

Bedford, Mark T.
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机构: Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA

Jenuwein, Thomas
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机构: Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA

Berger, Shelley L.
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h-index: 0
机构: Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA
机构:
[1] Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA
[2] Vienna Bioctr, Res Inst Mol Pathol, A-1030 Vienna, Austria
[3] Univ Texas, MD Anderson Canc Ctr, Dept Carcinogenesis, Smithville, TX 78957 USA
来源:
基金:
美国国家卫生研究院;
关键词:
D O I:
10.1038/nature06092
中图分类号:
O [数理科学和化学];
P [天文学、地球科学];
Q [生物科学];
N [自然科学总论];
学科分类号:
07 ;
0710 ;
09 ;
摘要:
p53, the tumour suppressor and transcriptional activator, is regulated by numerous post-translational modifications, including lysine methylation(1,2). Histone lysine methylation has recently been shown to be reversible; however, it is not known whether nonhistone proteins are substrates for demethylation. Here we show that, in human cells, the histone lysine-specific demethylase LSD1 (refs 3, 4) interacts with p53 to repress p53-mediated transcriptional activation and to inhibit the role of p53 in promoting apoptosis. We find that, in vitro, LSD1 removes both monomethylation (K370me1) and dimethylation (K370me2) at K370, a previously identified Smyd2-dependent monomethylation site(2). However, in vivo, LSD1 shows a strong preference to reverse K370me2, which is performed by a distinct, but unknown, methyltransferase. Our results indicate that K370me2 has a different role in regulating p53 from that of K370me1: K370me1 represses p53 function, whereas K370me2 promotes association with the coactivator 53BP1 (p53-binding protein 1) through tandem Tudor domains in 53BP1. Further, LSD1 represses p53 function through the inhibition of interaction of p53 with 53BP1. These observations show that p53 is dynamically regulated by lysine methylation and demethylation and that the methylation status at a single lysine residue confers distinct regulatory output. Lysine methylation therefore provides similar regulatory complexity for non-histone proteins and for histones.
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页码:105 / U80
页数:5
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