Akt phosphorylates the transcriptional repressor bmi1 to block its effects on the tumor-suppressing ink4a-arf locus.
Akt phosphorylates the transcriptional repressor bmi1 to block its effects on the tumor-suppressing ink4a-arf locus.
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DOI：
10.1126/scisignal.2003199
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发表时间：
2012-10-23
影响因子：
7.3
通讯作者：
Nimer SD
中科院分区：
文献类型：
--
作者：
Liu Y;Liu F;Yu H;Zhao X;Sashida G;Deblasio A;Harr M;She QB;Chen Z;Lin HK;Di Giandomenico S;Elf SE;Yang Y;Miyata Y;Huang G;Menendez S;Mellinghoff IK;Rosen N;Pandolfi PP;Hedvat CV;Nimer SD
Polycomb组蛋白Bmi 1是Ink 4a-Arf基因座的转录沉默子，其编码细胞周期调节因子p16 Ink 4a和肿瘤抑制因子p19 Arf。Bmi 1在肿瘤发生和干细胞自我更新中起关键作用。我们报告说，Akt在Ser 316处磷酸化人Bmi 1通过触发其与Ink 4a-Arf位点的解离而损害其功能，这导致组蛋白H2 A的泛素化降低，Bmi 1不能促进细胞增殖和肿瘤生长。此外，Akt介导的Bmi 1磷酸化也抑制了其促进造血干细胞和祖细胞自我更新的能力。我们的研究提供了一个机制，增加丰度的p16 Ink 4a和p19 Arf在癌细胞中看到一个激活的磷酸肌醇3-激酶Akt信号通路，并确定磷酸化事件和染色质结构之间的串扰。
The Polycomb group protein Bmi1 is a transcriptional silencer of the Ink4a-Arf locus, which encodes the cell cycle regulator p16Ink4a and the tumor suppressor p19Arf. Bmi1 plays a key role in oncogenesis and stem cell self-renewal. We report that phosphorylation of human Bmi1 at Ser316 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 p16Ink4a and p19Arf seen in cancer cells with an activated phosphoinositide 3-kinase to Akt signaling pathway and identifies crosstalk between phosphorylation events and chromatin structure.
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DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J
影响因子：
23.9
作者：
Lee, Jae Y.;Nakada, Daisuke;Yilmaz, Omer H.;Tothova, Zuzana;Joseph, Nancy M.;Lim, Megan S.;Gilliland, D. Gary;Morrison, Sean J.
通讯作者：
Morrison, Sean J.
影响因子：
64.5
作者：
Lee, TI;Jenner, RG;Young, RA
通讯作者：
Young, RA
影响因子：
56.9
作者：
Cha, TL;Zhou, BHP;Hung, MC
通讯作者：
Hung, MC
影响因子：
32.4
作者：
Iwama, A;Oguro, H;Nakauchi, H
通讯作者：
Nakauchi, H