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Down‐regulation of nuclear protein ICBP90 by p53/p21 Cip1/WAF1 ‐dependent DNA‐damage checkpoint signals contributes to cell cycle arrest at G1/S transition
Author(s) -
Arima Yoshimi,
Hirota Toru,
Bronner Christian,
Mousli Marc,
Fujiwara Toshiyoshi,
Niwa Shinichiro,
Ishikawa Hiroyuki,
Saya Hideyuki
Publication year - 2004
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1111/j.1356-9597.2004.00710.x
Subject(s) - cell cycle checkpoint , dna damage , biology , g2 m dna damage checkpoint , chek1 , microbiology and biotechnology , cell cycle , dna replication , dna repair , g1 phase , dna , cell , genetics
Checkpoints, which monitor DNA damage and regulate cell cycle progression, ensure genomic integrity and prevent the propagation of transformed cells. DNA damage activates the p53‐dependent checkpoint pathway that induces expression of p21 Cip1/WAF1 , resulting in cell cycle arrest at G1/S transition by inhibition of cdk activity and DNA replication. ICBP90 was identified as a nuclear protein that binds to the TopoII α gene promoter and is speculated to be involved in DNA replication. ICBP90 expression is cell cycle regulated in normal cells but stably high throughout cell cycle in various cancer cell lines. We here demonstrate that ICBP90 expression is down‐regulated by the p53/p21 Cip1/WAF1 ‐dependent DNA damage checkpoint signals. The reduction of ICBP90 appeared to be caused by both transcriptional suppression and protein degradation. Adenoviral expression of p21 Cip1/WAF1 directly led to ICBP90 reduction in p53 −/− HCT116 cells without DNA damage. Furthermore, ICPB90 depletion by RNA interference significantly blocked G1/S transition after DNA damage in HeLa cells. The down‐regulation of ICBP90 is an important mechanism for cell cycle arrest at G1/S transition, which is induced by the activation of a p53/p21 Cip1/WAF1 ‐dependent DNA‐damage checkpoint. Deregulation of ICBP90 may impair the control of G1/S transition during checkpoint activation and lead to genomic instability.