p27 is regulated independently of Skp2 in the absence of Cdk2

被引：10
|
作者：
Kotoshiba, Shuhei [1 ,7 ]
Gopinathan, Lakshmi [1 ]
Pfeiffenberger, Elisabeth [1 ]
Rahim, Anisa [6 ]
Vardy, Leah A. [6 ,8 ]
Nakayama, Keiko [3 ]
Nakayama, Keiichi I. [4 ,5 ]
Kaldis, Philipp [1 ,2 ,7 ]
机构：
[1] ASTAR, Inst Mol & Cell Biol, Singapore 138673, Singapore
[2] Natl Univ Singapore, Dept Biochem, Singapore 117597, Singapore
[3] Tohoku Univ, Dept Dev Genet, Grad Sch Med, Ctr Translat & Adv Anim Res,Aoba Ku, Sendai, Miyagi 980, Japan
[4] Kyushu Univ, Med Inst Bioregulat, Dept Mol & Cellular Biol, Higashi Ku, Fukuoka 8128582, Japan
[5] Japan Sci & Technol Agcy, CREST, Kawaguchi, Saitama 3320012, Japan
[6] ASTAR, Inst Med Biol, Singapore 138648, Singapore
[7] NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21702 USA
[8] Nanyang Technol Univ, Sch Biol Sci, Singapore 639798, Singapore
来源：
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH | 2014年 / 1843卷 / 02期
基金：
日本学术振兴会;
关键词：
Cyclin-dependent kinase; Knockout mice; Cdk2; Skp2; p27; DEPENDENT KINASE INHIBITOR; SCFSKP2 UBIQUITIN LIGASE; CELL-DIVISION; MICE LACKING; DNA-DAMAGE; CULLIN; 4A; G1; PHASE; S-PHASE; P27(KIP1); DEGRADATION;
D O I：
10.1016/j.bbamcr.2013.11.005
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：
Cyclin-dependent kinase 2 (Cdk2) is dispensable for mitotic cell cycle progression and Cdk2 knockout mice are viable due to the compensatory functions of other Cdlcs. In order to assess the role of Cdk2 under limiting conditions, we used Skp2 knockout mice that exhibit increased levels of Cdk inhibitor, p27K1P1, which is able to inhibit Cdk2 and Cdkl. Knockdown of Cdk2 abrogated proliferation of Skp2(-/-) mouse embryonic fibroblasts, encouraging us to generate Cdk2(-/-)Skp2(-/-) double knockout mice. Cdk2(-/-)Skp2(-/-) double knockout mice are viable and display similar phenotypes as Cdk2(-/-) and Skp2(-/-) mice. Unexpectedly, fibroblasts generated from Cdk2(-/-)Skp2(-/-) double knockout mice proliferated at normal rates. The increased stability of p27 observed in Skp2(-/-) MEFs was not observed in Cdk2(-/-)Skp2(-/-) double knockout fibroblasts indicating that in the absence of Cdk2, p27 is regulated by Skp2-independent mechanisms. Ablation of other ubiquitin ligases for p27 such as KPCI, DDBI, and Pirh2 did not restore stability of p27 in Cdk2(-/-)Skp2(-/-) MEFs. Our findings point towards novel and alternate pathways for p27 regulation. (C) 2013 Elsevier B.V. All rights reserved.
引用
收藏
页码：436 / 445
页数：10
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