RRC ID |
39374
|
Author |
Tominaga K, Morisaki H, Kaneko Y, Fujimoto A, Tanaka T, Ohtsubo M, Hirai M, Okayama H, Ikeda K, Nakanishi M.
|
Title |
Role of human Cds1 (Chk2) kinase in DNA damage checkpoint and its regulation by p53.
|
Journal |
J Biol Chem
|
Abstract |
In response to DNA damage, mammalian cells adopt checkpoint regulation, by phosphorylation and stabilization of p53, to delay cell cycle progression. However, most cancer cells that lack functional p53 retain an unknown checkpoint mechanism(s) by which cells are arrested at the G(2)/M phase. Here we demonstrate that a human homolog of Cds1/Rad53 kinase (hCds1) is rapidly phosphorylated and activated in response to DNA damage not only in normal cells but in cancer cells lacking functional p53. A survey of various cancer cell lines revealed that the expression level of hCds1 mRNA is inversely related to the presence of functional p53. In addition, transfection of normal human fibroblasts with SV40 T antigen or human papilloma viruses E6 or E7 causes a marked induction of hCds1 mRNA, and the introduction of functional p53 into SV40 T antigen- and E6-, but not E7-, transfected cells decreases the hCds1 level, suggesting that p53 negatively regulates the expression of hCds1. In cells without functional ataxia telangiectasia mutated (ATM) protein, phosphorylation and activation of hCds1 were observed in response to DNA damage induced by UV but not by ionizing irradiation. These results suggest that hCds1 is activated through an ATM-dependent as well as -independent pathway and that it may complement the function of p53 in DNA damage checkpoints in mammalian cells.
|
Volume |
274(44)
|
Pages |
31463-7
|
Published |
1999-10-29
|
DOI |
10.1074/jbc.274.44.31463
|
PII |
S0021-9258(19)51642-8
|
PMID |
10531348
|
MeSH |
Ataxia Telangiectasia Mutated Proteins
Cell Compartmentation
Cell Cycle*
Cell Cycle Proteins
Checkpoint Kinase 2
Chromosome Mapping
Chromosomes, Human, Pair 22
Cloning, Molecular
DNA Damage*
DNA-Binding Proteins
Enzyme Activation
Humans
Nuclear Proteins / metabolism
Phosphorylation
Protein Kinases / genetics
Protein Kinases / metabolism*
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism*
Tumor Suppressor Protein p53 / metabolism*
Tumor Suppressor Proteins
|
IF |
4.238
|
Times Cited |
76
|
WOS Category
|
BIOCHEMISTRY & MOLECULAR BIOLOGY
|
Resource |
Human and Animal Cells |
WI-38 |