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

doi:10.1007/s00018-010-0459-7

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

Toxicology and Cancer Biology

Research output: Contribution to journal › Article › peer-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 language	English
Pages (from-to)	475-488
Number of pages	14
Journal	Cellular and Molecular Life Sciences
Volume	68
Issue number	3
DOIs	https://doi.org/10.1007/s00018-010-0459-7
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

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10.1007/s00018-010-0459-7

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

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.",

keywords = "Akt, Arsenite, HIF-1α, Hsp70, p85α",

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

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{\textquoteright}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. +/+ −/− ",

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doi = "10.1007/s00018-010-0459-7",

language = "English",

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T1 - Arsenite stabilizes HIF-1α protein through p85α-mediated up-regulation of inducible Hsp70 protein expression

AU - Guo, Wei

AU - Yang, Zhuo

AU - Xia, Qing

AU - Liu, Jinyi

AU - Yu, Yonghui

AU - Li, Jingxia

AU - Zuo, Zhenghong

AU - Zhang, Dongyun

AU - Li, Xueyong

AU - Shi, Xianglin

AU - Huang, Chuanshu

N1 - 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. +/+ −/−

PY - 2011/2

Y1 - 2011/2

N2 - 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.

AB - 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.

KW - Akt

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KW - Hsp70

KW - p85α

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ER -

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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