p53 Regulates Hsp90β during arsenite-induced cytotoxicity in glutathione-deficient cells

Abstract

Abstractp53, 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 Hsp90β gene expression. Mutation analysis revealed a p53 binding site in the 5′flanking region responsible for the regulation of Hsp90β gene. Electrophoretic mobility shift assay showed that p53 is bound to Hsp90β 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 Hsp90β 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 Hsp90β, under GSH-deficient conditions which may play a role in arsenic-mediated pathogenesis.

Arsenite causes down‐regulation of Akt and c‐Fos, cell cycle dysfunction and apoptosis in glutathione‐deficient cells

“…Using GSH-deficient GCS-2 cells, we have previously demonstrated that arsenite induces ubiquitination and apoptotic cell death [cytochrome C leakage and DNA fragmentation; Habib et al, 2007] and that p53 regulates Hsp90β during arsenite-induced cytotoxicity [Habib et al, 2009]. In the current study, we show that arsenite down-regulates Akt and c-Fos by ubiquitination, decreases AP-1 activity and causes cell cycle dysregulation and apoptotic cell death.…”

Heat shock protein 90–mediated inactivation of nuclear factor-κB switches autophagy to apoptosis through becn1 transcriptional inhibition in selenite-induced NB4 cells

“…To identify possible reasons for this discrepancy, we checked the p53 status of these cell lines because the tumor suppressor p53 has been shown to function in the transcriptional repression of the hsp90 gene (Zhang et al , 2004 ; Habib, 2009 ). The results showed that our NB4 cell line expressed wild-type p53 and that nuclear p53 expression was increased after selenite exposure.…”

One Function—Multiple Mechanisms: The Manifold Activities of p53 as a Transcriptional Repressor

“…In addition to these primary p53 target genes, for a couple of genes direct DNA-binding of p53 to the promoter region in vivo was demonstrated for example for the p202- [ 43 ], PTTG1 - [ 44 ], PRC1 - [ 45 ], CHEK - [ 44 ], RAD51 - [ 46 , 47 ], hDDA3 - [ 48 ], Hsp90 β - [ 49 ], and LASP1 -gene [ 50 ]. Here interaction of p53 with its consensus sequence leads to transcriptional repression.…”