Prolyl hydroxylation by EglN2 destabilizes FOXO3a by blocking its interaction with the USP9x deubiquitinase

被引：105

作者：

Zheng, Xingnan ^{[1
]}

Zhai, Bo ^{[2
]}

Koivunen, Peppi ^{[3
]}

Shin, Sandra. J. ^{[4
]}

Lu, Gang ^{[5
]}

Liu, Jiayun ^{[5
]}

Geisen, Christoph ^{[5
]}

Chakraborty, Abhishek A. ^{[5
]}

Moslehi, Javid J. ^{[5
]}

Smalley, David M. ^{[6
]}

Wei, Xin ^{[7
]}

Chen, Xian ^{[7
]}

Chen, Zhengming ^{[8
]}

Beres, Justine M. ^{[1
]}

Zhang, Jing ^{[1
]}

Tsao, Jen Lan ^{[9
]}

Brenner, Mitchell C. ^{[9
]}

Zhang, Yuqing ^{[4
]}

Fan, Cheng ^{[1
]}

DePinho, Ronald A. ^{[10
]}

Paik, Jihye ^{[4
]}

Gygi, Steven P. ^{[2
]}

Kaelin, William G., Jr. ^{[5
,11
]}

Zhang, Qing ^{[1
,12
]}

机构：

[1] Univ N Carolina, Sch Med, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA

[2] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA

[3] Univ Oulu, Oulu Ctr Cell Matrix Res, Fac Biochem & Mol Med, Bioctr Oulu, FIN-90014 Oulu, Finland

[4] Weill Cornell Med Coll, Dept Pathol & Lab Med, New York, NY 10065 USA

[5] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[6] Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA

[7] Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA

[8] Weill Cornell Med Coll, Dept Publ Hlth, Div Biostat & Epidemiol, New York, NY 10065 USA

[9] Fibrogen Inc, San Francisco, CA 94158 USA

[10] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA

[11] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA

[12] Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA

来源：

GENES & DEVELOPMENT | 2014年 / 28卷 / 13期

基金：

美国国家卫生研究院;

关键词：

EglN2; FOXO3a; USP9x; prolyl hydroxylation; Cyclin D1; breast cancer; ESTROGEN-RECEPTOR-ALPHA; TRANSCRIPTION FACTOR; BREAST-CANCER; PROMOTES TUMORIGENESIS; PROLINE HYDROXYLATION; HIF-ALPHA; C-ELEGANS; HYPOXIA; INHIBITION; KINASE;

D O I：

10.1101/gad.242131.114

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

The three EglN prolyl hydroxylases (EglN1, EglN2, and EglN3) regulate the stability of the REF transcription factor. We recently showed that loss of EglN2, however, also leads to down-regulation of Cyclin D1 and decreased cell proliferation in a HIF-independent manner. Here we report that EglN2 can hydroxylate FOXO3a on two specific prolyl residues in vitro and in vivo. Hydroxylation of these sites prevents the binding of USP9x deubiquitinase, thereby promoting the proteasomal degradation of FOXO3a. FOXO transcription factors can repress Cyclin D1 transcription. Failure to hydroxylate FOXO3a promotes its accumulation in cells, which in turn suppresses Cyclin D1 expression. These findings provide new insights into post-transcriptional control of FOXO3a and provide a new avenue for pharmacologically altering Cyclin D1 activity.

引用

页码：1429 / 1444

页数：16

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