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Fzrl/Cdh links to redox-independent Cdc25C ubiquitination and degradation induced by arsenic.

Authors
Chen-F; Lu-Y; Castranova-V; Ding-M; Shi-XL
Source
Free Radic Biol Med 2004 Jan; 37(Suppl 1):S123
NIOSHTIC No.
20028048
Abstract
Regulated protein degradation is fundamental to cell growth, cell cycle and carcinogenic transformation. Therefore, targeting the destruction of proteins, particularly the proteins mediating cell cycle or malignant transformation, has been a major focus of cancer therapy. Arsenic, an established carcinogen as well as a chemotherapeutic reagent for certain types of cancer, has been previously shown to be able to induce oxidative stress that tips the balance of intracellular redox status. In this report, we demonstrated that arsenic delays cell cycle reentry into G1 phase from G2/M phase through the inducible ubiquitination and degradation of Cdc25C, a key regulatory protein governing the exit of the cells from mitosis. The arsenic-induced Cdc25C degradation could not be interfered by the pretreatment of the cells with antioxidants, such as NAC. Immunoprecipitation indicates an in vivo association of Cdc25C with Fzr/Cdh1, a substrate recognition subunit of mitotic APC ubiquitin ligase complex. Silencing Fzr/Cdh1 expression by siRNA-induced RNA interference not only partially protected Cdc25C from proteasomal degradation but also substantially decreased ubiquitin conjugating activity of the cell lysates from arsenic-challenged cells. Thus, the redox-independent ubiquitination and degradation of Cdc25C is mediated by Fzr/Cdh1 in cellular response to arsenic. The capability of arsenic in inducing Cdc25C ubiquitination and degradation can provide a novel mechanistic evidence for the therapeutic usefulness of arsenic for certain cancer.
Keywords
Arsenic-compounds; Proteins; Protein-biochemistry; Carcinogenesis; Genotoxic-effects
CODEN
FRBMEH
CAS No.
7440-38-2
Publication Date
20040101
Document Type
Abstract; Conference/Symposia Proceedings
Fiscal Year
2004
NTIS Accession No.
NTIS Price
ISSN
0891-5849
NIOSH Division
HELD
Source Name
Free Radical Biology and Medicine
State
WV
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