Arsenite-induced Cdc25C degradation is through the KEN-box and ubiquitin-proteasome pathway.
Arsenite is a known human carcinogen that induces tumorigenesis through either a genotoxic or an epigenetic mechanism. In this study, the effect of arsenite on cell cycle regulation and the mechanisms that contribute to this effect were investigated. Treatment of the cells with arsenite suppressed cell proliferation and reduced cell viability in a dose- or time-dependent manner. Analysis of cell cycle profile and cell cycle regulatory proteins indicated that arsenite arrested the cell cycle at G(2)/M phase, partially through induction of cell division cycle 25 (Cdc25) isoform C (Cdc25C) degradation via ubiquitin-proteasome pathways. Mutation of the putative KEN box within the region 151 to 157 of human Cdc25C or treatment of the cells with a peptide competitor encompassing the KEN box partially inhibited arsenite-induced ubiquitination of Cdc25C. Thus, these results indicate that the regulated ubiquitination of Cdc25C may be involved in the arsenite-induced proteolytic down-regulation of Cdc25C activity in the G(2)/M phase of the cell cycle and suggest a link between cell cycle and the carcinogenic effects of arsenite.
Chen
Fei
F
Health Effects Laboratory Division, National Institute for Occupational Safety and Health, 1095 Willowdale Road, Morgantown, WV 26505, USA. lfd3@cdc.gov
Zhang
Zhuo
Z
Bower
Jacquelyn
J
Lu
Yongju
Y
Leonard
Stephen S
SS
Ding
Min
M
Castranova
Vince
V
Piwnica-Worms
Helen
H
Shi
Xianglin
X
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D020816:Amino Acid Motifs; D018053:Arsenites / Q000494:pharmacology*; D015153:Blotting, Western; D064199:Cdc20 Proteins; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D016193:G1 Phase; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D008938:Mitosis / Q000187:drug effects; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010455:Peptides / Q000737:chemistry; D010766:Phosphorylation; D011233:Precipitin Tests; D016192:Resting Phase, Cell Cycle; D029701:Saccharomyces cerevisiae Proteins; D013997:Time Factors; D025801:Ubiquitin / Q000378:metabolism; D020687:cdc25 Phosphatases / Q000378:metabolism*
D018053:Arsenites; C577495:CDC20 protein, S cerevisiae; D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins; D010455:Peptides; D029701:Saccharomyces cerevisiae Proteins; D025801:Ubiquitin; C067713:lactacystin; C517009:CDC25C protein, human; D020687:cdc25 Phosphatases; C015001:arsenite; D000111:Acetylcysteine