Cooperative functions of Chk1 and Chk2 reduce tumour susceptibility in vivo

被引：47

作者：

Niida, Hiroyuki ^{[8
]}

Murata, Kazuhiro

Shimada, Midori

Ogawa, Kumiko ^{[2
]}

Ohta, Kumiko ^{[3
]}

Suzuki, Kyoko ^{[3
]}

Fujigaki, Hidetsugu ^{[4
]}

Khaw, Aik Kia ^{[5
]}

Banerjee, Birendranath ^{[5
]}

Hande, M. Prakash ^{[5
]}

Miyamoto, Tomomi ^{[6
,7
]}

Miyoshi, Ichiro ^{[6
,7
]}

Shirai, Tomoyuki ^{[2
]}

Motoyama, Noboru ^{[3
]}

Delhase, Mireille

Appella, Ettore ^{[4
]}

Nakanishi, Makoto ^{[1
]}

机构：

[1] Nagoya City Univ, Dept Cell Biol, Grad Sch Med Sci, Mizuho Ku, Nagoya, Aichi 4678601, Japan

[2] Nagoya City Univ, Dept Expt Pathol & Tumor Biol, Mizuho Ku, Nagoya, Aichi 4678601, Japan

[3] Natl Ctr Geriatr & Gerontol, Dept Cognit Brain Sci, Aichi, Japan

[4] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA

[5] Natl Univ Singapore, Dept Physiol, Yong Loo Lin Sch Med, Singapore 117548, Singapore

[6] Nagoya City Univ, Dept Comparat & Expt Med, Grad Sch Med Sci, Mizuho Ku, Nagoya, Aichi 4678601, Japan

[7] Nagoya City Univ, Ctr Anim Sci, Grad Sch Med Sci, Mizuho Ku, Nagoya, Aichi 4678601, Japan

[8] Hamamatsu Univ Sch Med, Dept Biochem, Higashi Ku, Shizuoka, Japan

来源：

EMBO JOURNAL | 2010年 / 29卷 / 20期

关键词：

apoptosis; cancer; checkpoint; DNA damage; senescence; ONCOGENE-INDUCED SENESCENCE; DNA-DAMAGE CHECKPOINT; BREAST-CANCER; P53; KINASE; PHOSPHORYLATION; ACTIVATION; TUMORIGENESIS; PROTEIN; CELLS;

D O I：

10.1038/emboj.2010.218

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：

Although the linkage of Chk1 and Chk2 to important cancer signalling suggests that these kinases have functions as tumour suppressors, neither Chk1(+/-) nor Chk2(-/-) mice show a predisposition to cancer under unperturbed conditions. We show here that Chk1(+/-) Chk2(-/-) and Chk1(+/-) Chk2(+/-) mice have a progressive cancer-prone phenotype. Deletion of a single Chk1 allele compromises G2/M checkpoint function that is not further affected by Chk2 depletion, whereas Chk1 and Chk2 cooperatively affect G1/S and intra-S phase checkpoints. Either or both of the kinases are required for DNA repair depending on the type of DNA damage. Mouse embryonic fibroblasts from the double-mutant mice showed a higher level of p53 with spontaneous DNA damage under unperturbed conditions, but failed to phosphorylate p53 at S23 and further induce p53 expression upon additional DNA damage. Neither Chk1 nor Chk2 is apparently essential for p53- or Rb-dependent oncogene-induced senescence. Our results suggest that the double Chk mutation leads to a high level of spontaneous DNA damage, but fails to eliminate cells with damaged DNA, which may ultimately increase cancer susceptibility independently of senescence. The EMBO Journal (2010) 29, 3558-3570. doi:10.1038/emboj.2010.218; Published online 10 September 2010Subject Categories: genome stability & dyanamics; molecular biology of disease

引用

页码：3558 / 3570

页数：13

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