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Heat induction of the unphosphorylated form of hypoxia-inducible factor-1alpha is dependent on heat shock protein-90 activity


Katschinski, D M; Le, L; Heinrich, D; Wagner, K F; Hofer, T; Schindler, S G; Wenger, R H (2002). Heat induction of the unphosphorylated form of hypoxia-inducible factor-1alpha is dependent on heat shock protein-90 activity. Journal of Biological Chemistry, 277(11):9262-9267.

Abstract

Hypoxia-inducible factor (HIF)-1alpha is the oxygen-sensitive subunit of HIF-1, a transcriptional master regulator of oxygen homeostasis. Oxygen-dependent prolyl hydroxylation targets HIF-1alpha for ubiquitinylation and proteasomal degradation. Unexpectedly, we found that exposing mice to elevated temperatures resulted in a strong HIF-1alpha induction in kidney, liver, and spleen. To elucidate the molecular mechanisms responsible for this effect, HepG2 hepatoma cells were exposed to different temperatures (34-42 degrees C) under normoxic (20% O(2)) or hypoxic (3% O(2)) conditions. Heat was sufficient to stabilize mainly a phosphatase-resistant, low molecular weight form of HIF-1alpha (termed HIF-1alpha(a)). Heat-induced HIF-1alpha(a) accumulated in the nucleus but neither bound to DNA nor trans-activated reporter or target gene expression, demonstrating the need for post-translational modifications for these functions. The protein banding pattern of heat-induced HIF-1alpha in immunoblot analyses was clearly distinct from the HIF-1alpha pattern after prolyl hydroxylase inhibition (by hypoxia or iron chelation/replacement) or following proteasome inhibition, suggesting that heat stabilizes HIF-1alpha by a novel mechanism. Inhibition of the ATP-dependent chaperone activity of HSP90 by novobiocin or geldanamycin prevented heat-induced as well as hypoxia-induced HIF-1alpha accumulation, indicating a common role of the HSP90 chaperone activity in HIF-1alpha stabilization by these two environmental parameters.

Abstract

Hypoxia-inducible factor (HIF)-1alpha is the oxygen-sensitive subunit of HIF-1, a transcriptional master regulator of oxygen homeostasis. Oxygen-dependent prolyl hydroxylation targets HIF-1alpha for ubiquitinylation and proteasomal degradation. Unexpectedly, we found that exposing mice to elevated temperatures resulted in a strong HIF-1alpha induction in kidney, liver, and spleen. To elucidate the molecular mechanisms responsible for this effect, HepG2 hepatoma cells were exposed to different temperatures (34-42 degrees C) under normoxic (20% O(2)) or hypoxic (3% O(2)) conditions. Heat was sufficient to stabilize mainly a phosphatase-resistant, low molecular weight form of HIF-1alpha (termed HIF-1alpha(a)). Heat-induced HIF-1alpha(a) accumulated in the nucleus but neither bound to DNA nor trans-activated reporter or target gene expression, demonstrating the need for post-translational modifications for these functions. The protein banding pattern of heat-induced HIF-1alpha in immunoblot analyses was clearly distinct from the HIF-1alpha pattern after prolyl hydroxylase inhibition (by hypoxia or iron chelation/replacement) or following proteasome inhibition, suggesting that heat stabilizes HIF-1alpha by a novel mechanism. Inhibition of the ATP-dependent chaperone activity of HSP90 by novobiocin or geldanamycin prevented heat-induced as well as hypoxia-induced HIF-1alpha accumulation, indicating a common role of the HSP90 chaperone activity in HIF-1alpha stabilization by these two environmental parameters.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:2002
Deposited On:11 Feb 2008 12:23
Last Modified:26 Aug 2016 07:32
Publisher:American Society for Biochemistry and Molecular Biology
ISSN:0021-9258
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1074/jbc.M110377200
PubMed ID:11779866

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