Chk2 is a tumor suppressor that regulates apoptosis in both an ataxia telangiectasia mutated (ATM)-dependent and an ATM-independent manner.
In response to ionizing radiation (IR), the tumor suppressor p53 is stabilized and promotes either cell cycle arrest or apoptosis. Chk2 activated by IR contributes to this stabilization, possibly by direct phosphorylation. Like p53, Chk2 is mutated in patients with Li-Fraumeni syndrome. Since the ataxia telangiectasia mutated (ATM) gene is required for IR-induced activation of Chk2, it has been assumed that ATM and Chk2 act in a linear pathway leading to p53 activation. To clarify the role of Chk2 in tumorigenesis, we generated gene-targeted Chk2-deficient mice. Unlike ATM(-/-) and p53(-/-) mice, Chk2(-/-) mice do not spontaneously develop tumors, although Chk2 does suppress 7,12-dimethylbenzanthracene-induced skin tumors. Tissues from Chk2(-/-) mice, including those from the thymus, central nervous system, fibroblasts, epidermis, and hair follicles, show significant defects in IR-induced apoptosis or impaired G(1)/S arrest. Quantitative comparison of the G(1)/S checkpoint, apoptosis, and expression of p53 proteins in Chk2(-/-) versus ATM(-/-) thymocytes suggested that Chk2 can regulate p53-dependent apoptosis in an ATM-independent manner. IR-induced apoptosis was restored in Chk2(-/-) thymocytes by reintroduction of the wild-type Chk2 gene but not by a Chk2 gene in which the sites phosphorylated by ATM and ataxia telangiectasia and rad3(+) related (ATR) were mutated to alanine. ATR may thus selectively contribute to p53-mediated apoptosis. These data indicate that distinct pathways regulate the activation of p53 leading to cell cycle arrest or apoptosis.
Hirao
Atsushi
A
Department of Medical Biophysics, Ontario Cancer Institute, University of Toronto, Ontario M5G 2C1, Canada.
Cheung
Alison
A
Duncan
Gordon
G
Girard
Pierre-Marie
PM
Elia
Andrew J
AJ
Wakeham
Andrew
A
Okada
Hitoshi
H
Sarkissian
Talin
T
Wong
Jorge A
JA
Sakai
Takashi
T
De Stanchina
Elisa
E
Bristow
Robert G
RG
Suda
Toshio
T
Lowe
Scott W
SW
Jeggo
Penny A
PA
Elledge
Stephen J
SJ
Mak
Tak W
TW
D015127:9,10-Dimethyl-1,2-benzanthracene; D000409:Alanine / Q000737:chemistry; D000818:Animals; D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002273:Carcinogens; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D064447:Checkpoint Kinase 2; D004268:DNA-Binding Proteins; D004307:Dose-Response Relationship, Radiation; D005260:Female; D016158:Genes, p53; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D008957:Models, Genetic; D009154:Mutation; D009374:Neoplasms, Experimental / Q000517:prevention & control; D010766:Phosphorylation; D011485:Protein Binding; D011494:Protein Kinases / Q000378:metabolism / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology; D013997:Time Factors; D014018:Tissue Distribution; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000502:physiology*
D002273:Carcinogens; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D015127:9,10-Dimethyl-1,2-benzanthracene; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; C578633:Chek2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D000409:Alanine