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Arsenite causes down‐regulation of Akt and c‐Fos, cell cycle dysfunction and apoptosis in glutathione‐deficient cells
Author(s) -
Habib Geetha M.
Publication year - 2010
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.22548
Subject(s) - protein kinase b , apoptosis , microbiology and biotechnology , cell cycle , cyclin dependent kinase 6 , pi3k/akt/mtor pathway , biology , cyclin dependent kinase , kinase , programmed cell death , cyclin d , arsenite , cell growth , signal transduction , cancer research , chemistry , biochemistry , arsenic , organic chemistry
Arsenic is a well‐known environmental toxicant but the mechanism by which it causes cytotoxicity is poorly understood. Arsenite induces apoptosis in glutathione (GSH)‐deficient GCS‐2 cells by causing cell cycle dysfunction and down‐regulating critical signaling pathways. This study was designed to examine the effect of arsenite on redox‐sensitive phosphatidylinositol 3‐kinase (PI3K)/Akt, a signaling pathway involved in cell survival and growth, and transcription factor, activating protein‐1 (AP‐1). Arsenite significantly diminished Akt and c‐Fos levels and caused accelerated degradation of these proteins by ubiquitnation. Arsenite also induced cell cycle arrest and apoptosis. The cell cycle arrest involved the down‐regulation of cyclin A2, cyclin D1, cyclin E, cyclin dependent kinases (CDK) 2, CDK4, and CDK6. Apoptosis involved down‐regulation of anti‐apoptotic proteins Bcl‐2, Bcl‐xL, survivin, and inhibitor of apoptosis protein (IAP) and up‐regulation of pro‐apoptotic protein Bax. Taken together, our results suggest that a possible mechanism of arsenite‐induced toxicity under low/no GSH conditions, is to negatively regulate GCS‐2 cell proliferation by attenuating Akt and AP‐1 by ubiquitination and causing cell cycle dysfunction and apoptosis. J. Cell. Biochem. 110: 363–371, 2010. © 2010 Wiley‐Liss, Inc.