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.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Zhang D,Li J,Costa M,Gao J,Huang Cdoi
10.1158/0008-5472.CAN-09-0448subject
Has Abstractpub_date
2010-01-15 00:00:00pages
813-23issue
2eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-09-0448journal_volume
70pub_type
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