CANCER Akt Phosphorylates the Transcriptional Repressor Bmi1 to Block Its Effects on the Tumor-Suppressing Ink4a-Arf Locus

被引：48

作者：

Liu, Yan ^{[1
,2
]}

Liu, Fan ^{[1
]}

Yu, Hao ^{[2
]}

Zhao, Xinyang ^{[1
]}

Sashida, Goro ^{[1
]}

Deblasio, Anthony ^{[1
]}

Harr, Michael ^{[1
]}

She, Qing-Bai ^{[1
]}

Chen, Zhenbang ^{[3
]}

Lin, Hui-Kuan ^{[3
]}

Di Giandomenico, Silvana ^{[1
]}

Elf, Shannon E. ^{[1
]}

Yang, Youyang ^{[1
]}

Miyata, Yasuhiko ^{[1
]}

Huang, Gang ^{[1
]}

Menendez, Silvia ^{[1
]}

Mellinghoff, Ingo K. ^{[4
]}

Rosen, Neal ^{[1
]}

Pandolfi, Pier Paolo ^{[3
]}

Hedvat, Cyrus V. ^{[5
]}

Nimer, Stephen D. ^{[1
,6
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Sloan Kettering Inst, Mol Pharmacol & Chem Program, New York, NY 10065 USA

[2] Indiana Univ Sch Med, Herman B Wells Ctr Pediat Res, Dept Pediat, Indianapolis, IN 46202 USA

[3] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA

[4] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA

[5] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA

[6] Univ Miami, Miller Sch Med, Sylvester Comprehens Canc Ctr, Miami, FL 33136 USA

来源：

SCIENCE SIGNALING | 2012年 / 5卷 / 247期

关键词：

HEMATOPOIETIC STEM-CELLS; POLYCOMB GROUP PROTEINS; MYC TRANSGENIC MICE; RNA-POLYMERASE-II; SELF-RENEWAL; DEVELOPMENTAL REGULATORS; CHROMATIN-ASSOCIATION; CELLULAR SENESCENCE; TUMORIGENESIS; LEUKEMIA;

D O I：

10.1126/scisignal.2003199

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：

The Polycomb group protein Bmi1 is a transcriptional silencer of the Ink4a-Arf locus, which encodes the cell cycle regulator p16(Ink4a) and the tumor suppressor p19(Arf). Bmi1 plays a key role in oncogenesis and stem cell self-renewal. We report that phosphorylation of human Bmi1 at Ser(316) by Akt impaired its function by triggering its dissociation from the Ink4a-Arf locus, which resulted in decreased ubiquitylation of histone H2A and the inability of Bmi1 to promote cellular proliferation and tumor growth. Moreover, Akt-mediated phosphorylation of Bmi1 also inhibited its ability to promote self-renewal of hematopoietic stem and progenitor cells. Our study provides a mechanism for the increased abundance of p16(Ink4a) and p19(Arf) seen in cancer cells with an activated phosphoinositide 3-kinase to Akt signaling pathway and identifies crosstalk between phosphorylation events and chromatin structure.

引用

页数：10

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