Title: JNK1 mediates degradation HIF-1alpha by a VHL-independent mechanism that involves the chaperones Hsp90/Hsp70.
Authors: Zhang, Dongyun; Li, Jingxia; Costa, Max; Gao, Jimin; Huang, Chuanshu
Published In Cancer Res, (2010 Jan 15)
Abstract: Hypoxia-inducible factor-1alpha (HIF-1alpha) is a master transcription factor that is critical for the regulation of a variety of cellular functions. HIF-1alpha is rapidly degraded under normoxic conditions by ubiquitin-mediated proteasome pathway controlled by the tumor suppressor von Hippel Lindau (VHL). Several recent studies reveal that heat-shock proteins (Hsp) can regulate HIF-1alpha protein degradation by a VHL-independent pathway. Here, we demonstrate that the stress kinase c-Jun NH(2)-terminal kinase 1 (JNK1) is required for Hsp-dependent regulation of HIF-1alpha. Stabilization of HIF-1alpha was impaired in JNK1-/- cells but could be rescued by JNK1 reconstitution under hypoxic conditions. These effects could be phenocopied in other cell settings by JNK1 silencing. Accordingly, HIF-1 transcriptional activity and target gene expression were dramatically reduced in JNK1-/- cells. Further, decreased levels of endogenous Hsp90/Hsp70 proteins in JNK1-/- cells affected the protective roles of these chaperones in stabilizing newly synthesized HIF-1alpha, whereas enforced expression of Hsp90/Hsp70 in JNK1-/- cells increased HIF-1alpha stability relative to parental control cells. Furthering this connection, we also found that defective expression of the Hsp90 acetyltransferase HDAC6 in JNK1-/- cells was associated with reduced Hsp90 chaperone activity. Taken together, our studies define a novel function for JNK1 in regulating HIF-1alpha turnover by a VHL-independent mechanism.
PubMed ID: 20068160
MeSH Terms: Animals; Carcinogens/toxicity; Cell Hypoxia/physiology; Cell Line, Tumor; HSP70 Heat-Shock Proteins/metabolism*; HSP90 Heat-Shock Proteins/metabolism*; HeLa Cells; Histone Deacetylase 6; Histone Deacetylases/biosynthesis; Humans; Hypoxia-Inducible Factor 1, alpha Subunit/biosynthesis; Hypoxia-Inducible Factor 1, alpha Subunit/genetics; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism*; Mice; Mitogen-Activated Protein Kinase 8/genetics; Mitogen-Activated Protein Kinase 8/metabolism*; Nickel/toxicity; RNA, Messenger/biosynthesis; RNA, Messenger/genetics; Transcriptional Activation; Transfection; Von Hippel-Lindau Tumor Suppressor Protein/metabolism