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 language | English |
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Pages (from-to) | 475-488 |
Number of pages | 14 |
Journal | Cellular and Molecular Life Sciences |
Volume | 68 |
Issue number | 3 |
DOIs | |
State | Published - 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