Arsenite-induced Cdc25C degradation is through the KEN-box and ubiquitin-proteasome pathway

Fei Chen, Zhuo Zhang, Jacquelyn Bower, Yongju Lu, Stephen S. Leonard, Min Ding, Vince Castranova, Helen Piwnica-Worms, Xianglin Shi

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Abstract

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 G2/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 G2/M phase of the cell cycle and suggest a link between cell cycle and the carcinogenic effects of arsenite.

Original languageEnglish (US)
Pages (from-to)1990-1995
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number4
DOIs
StatePublished - Feb 19 2002

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Proteasome Endopeptidase Complex
Ubiquitin
Protein Isoforms
Cell Cycle
G2 Phase
Ubiquitination
Cell Division
Cell Cycle Proteins
arsenite
Epigenomics
Carcinogens
Cell Survival
Carcinogenesis
Down-Regulation
Cell Proliferation
Peptides
Mutation

ASJC Scopus subject areas

  • General

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Arsenite-induced Cdc25C degradation is through the KEN-box and ubiquitin-proteasome pathway. / Chen, Fei; Zhang, Zhuo; Bower, Jacquelyn; Lu, Yongju; Leonard, Stephen S.; Ding, Min; Castranova, Vince; Piwnica-Worms, Helen; Shi, Xianglin.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 99, No. 4, 19.02.2002, p. 1990-1995.

Research output: Contribution to journalArticle

Chen, Fei ; Zhang, Zhuo ; Bower, Jacquelyn ; Lu, Yongju ; Leonard, Stephen S. ; Ding, Min ; Castranova, Vince ; Piwnica-Worms, Helen ; Shi, Xianglin. / Arsenite-induced Cdc25C degradation is through the KEN-box and ubiquitin-proteasome pathway. In: Proceedings of the National Academy of Sciences of the United States of America. 2002 ; Vol. 99, No. 4. pp. 1990-1995.
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AU - Leonard, Stephen S.

AU - Ding, Min

AU - Castranova, Vince

AU - Piwnica-Worms, Helen

AU - Shi, Xianglin

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N2 - 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 G2/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 G2/M phase of the cell cycle and suggest a link between cell cycle and the carcinogenic effects of arsenite.

AB - 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 G2/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 G2/M phase of the cell cycle and suggest a link between cell cycle and the carcinogenic effects of arsenite.

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