부산대학교 도서관

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.abb.2008.10.024 Byline: Geetha M. Habib Keywords: Glutathione; p53; Arsenite; ATM; MAPK; Hsp90; Phosphorylation; Signal transduction; siRNA Abstract: p53, a tumor suppressor and transcription factor, is a critical modulator in the cellular response to stress. Exposure of glutathione-deficient GCS-2 cells to arsenite significantly phosphorylated and stabilized p53. In addition, p53 transcriptionally repressed Hsp90[beta] gene expression. Mutation analysis revealed a p53 binding site in the 5' flanking region responsible for the regulation of Hsp90[beta] gene. Electrophoretic mobility shift assay showed that p53 is bound to Hsp90[beta] promoter region. ATM kinase, a major determinant in the modulation of p53 specifically affected its phosphorylation at Ser-15. ATM kinase-mediated phosphorylation of p53 is regulated through phosphorylation of Chk2. Down-regulation of ATM and Chk2 by their small interfering RNAs (siRNAs) attenuated the arsenite-induced phosphorylation of p53 and restored Hsp90[beta] mRNA levels. Taken together, these findings suggest that arsenite acts through ATM and Chk2 to induce phosphorylation of p53. This results in the transcriptional repression of Hsp90[beta], under GSH-deficient conditions which may play a role in arsenic-mediated pathogenesis. Author Affiliation: Department of Pathology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA Article History: Received 21 May 2008; Revised 2 October 2008