Regulation of the antioncogenic Chk2 kinase by the oncogenic Wip1 phosphatase

被引:168
作者
Fujimoto, H.
Onishi, N.
Kato, N.
Takekawa, M.
Xu, X. Z.
Kosugi, A.
Kondo, T.
Imamura, M.
Oishi, I.
Yoda, A.
Minami, Y.
机构
[1] Kobe Univ, Grad Sch Med, Fac Med Sci, Dept Genome Sci,Chou Ku, Kobe, Hyogo 6500017, Japan
[2] Univ Tokyo, Inst Med Sci, Div Mol Cell Signalling, Minato Ku, Tokyo 1088639, Japan
[3] Japan Sci & Technol Corp, PRESTO, Kawaguchi, Saitama 3320012, Japan
[4] Osaka Univ, Fac Med, Sch Allied Hlth Sci, Suita, Osaka 5650871, Japan
[5] Hokkaido Univ, Grad Sch Med, Dept Gastroenterol, Kita Ku, Sapporo, Hokkaido 0608638, Japan
[6] Hokkaido Univ, Grad Sch Med, Dept Hematol, Kita Ku, Sapporo, Hokkaido 0608638, Japan
关键词
D O I
10.1038/sj.cdd.4401801
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 antioncogenic Chk2 kinase plays a crucial role in DNA damage-induced cell-cycle checkpoint regulation. Here we show that Chk2 associates with the oncogenic protein Wip1 (wild-type p53-inducible phosphatase 1) (PPM1D), a p53-inducible protein phosphatase. Phosphorylation of Chk2 at threonine68 (Thr68), a critical event for Chk2 activation, which is normally induced by DNA damage or overexpression of Chk2, is inhibited by expression of wild-type (WT), but not a phosphatase-deficient mutant (D314A) of Wip1 in cultured cells. Furthermore, an in vitro phosphatase assay revealed that Wip1 ( WT), but not Wip1 (D314A), dephosphorylates Thr68 on phosphorylated Chk2 in vitro, resulting in the inhibition of Chk2 kinase activity toward glutathione S-transferase-Cdc25C. Moreover, inhibition of Wip1 expression by RNA interference results in abnormally sustained Thr68 phosphorylation of Chk2 and increased susceptibility of cells in response to DNA damage, indicating that Wip1 acts as a negative regulator of Chk2 in response to DNA damage.
引用
收藏
页码:1170 / 1180
页数:11
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