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Molecular and Cellular Biology, February 2001, p. 1066-1076, Vol. 21, No. 4
Department of Biological Sciences, Columbia
University, New York, New York 10027,1 and
Institute of Biomedical Sciences, Academica Sinica, Nankang,
Taipei 11529, Taiwan2
Received 1 August 2000/Returned for modification 13 September
2000/Accepted 10 November 2000
Both fission yeast and mammalian cells require the function of the
checkpoint kinase CHK1 for G2 arrest after DNA damage. The
tumor suppressor p53, a well-studied stress response factor, has also
been shown to play a role in DNA damage G2 arrest, although in a manner that is probably independent of CHK1. p53, however, can be
phosphorylated and regulated by both CHK1 as well as another checkpoint
kinase, hCds1 (also called CHK2). It was therefore of interest to
determine whether reciprocally, p53 affects either CHK1 or CHK2. We
found that induction of p53 either by diverse stress signals or
ectopically using a tetracycline-regulated promoter causes a marked
reduction in CHK1 protein levels. CHK1 downregulation by p53 occurs as
a result of reduced CHK1 RNA accumulation, indicating that repression
occurs at the level of transcription. Repression of CHK1 by p53
requires p21, since p21 alone is sufficient for this to occur and cells
lacking p21 cannot downregulate CHK1. Interestingly, pRB is also
required for CHK1 downregulation, suggesting the possible involvement
of E2F-dependent transcription in the regulation of CHK1. Our results
identify a new repression target of p53 and suggest that p53 and CHK1
play interdependent and complementary roles in regulating both the
arrest and resumption of G2 after DNA damage.
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.4.1066-1076.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
p53 Down-Regulates CHK1 through p21 and the
Retinoblastoma Protein
*
Corresponding author. Mailing address: Department of
Biological Sciences, Columbia University, New York, NY 10027. Phone: (212) 853-2557. Fax: (212) 865-8246. E-mail:
clp3{at}columbia.edu.
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