Arsenite stabilizes HIF-1α protein through p85α-mediated up-regulation of inducible Hsp70 protein expression

Wei Guo, Zhuo Yang, Qing Xia, Jinyi Liu, Yonghui Yu, Jingxia Li, Zhenghong Zuo, Dongyun Zhang, Xueyong Li, Xianglin Shi, Chuanshu Huang

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Hypoxia-inducible factor-1α (HIF-1α) has been reported to regulate over 100 gene expressions in response to hypoxia and other stress conditions. In the present study, we found that arsenite could induce HIF-1α protein accumulation in both mouse epidermal Cl41 cells and mouse embryonic fibroblasts (MEFs). Knockout of p85α, a regulatory subunit of PI-3K, in MEFs (p85α-/-) dramatically decreased the arsenite-induced HIF-1α accumulation, indicating that p85α is crucial for arsenite effects on the stabilization of HIF-1α protein. Our further studies suggest that arsenite could induce inducible Hsp70 expression, and transfection of inducible Hsp70 into p85α-/- MEFs could restore HIF-1α protein accumulation. Moreover, the results using EMSA and Supershift assays indicate that p85α is crucial for arsenite-induced activation of the heat-shock transcription factor 1 (HSF-1), which is responsible for transcription of inducible Hsp70. Taken together, p85α-mediated HIF-1α stabilization upon arsenite exposure is specifically through HSF-1 activation and subsequent up-regulation of the inducible Hsp70 expression.

Original languageEnglish
Pages (from-to)475-488
Number of pages14
JournalCellular and Molecular Life Sciences
Volume68
Issue number3
DOIs
StatePublished - Feb 2011

Bibliographical note

Funding Information:
This work was supported in part by grants from NIH/NCI CA112557, CA119028-05S110, and from NIH/NIEHS ES012451, ES010344. We thank Dr. Hector R. Wong (Children’s Hospital Medical Center, Cincinnati, OH, USA) for providing inducible Hsp70 constructs and HSF-1 and HSF-1 cells, and Dr. Alice Liu (Rutgers State University of New Jersey, Piscataway, NJ, USA) for providing Hsp70 luciferase reporter plasmid. We also thank Ms. Nedda Tichi for her critical reading of the manuscript. +/+ −/−

Keywords

  • Akt
  • Arsenite
  • HIF-1α
  • Hsp70
  • p85α

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Cellular and Molecular Neuroscience
  • Cell Biology

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