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COMMD1 Promotes pVHL and O2-Independent Proteolysis of HIF-1alpha via HSP90/70.

ABSTRACT: The Copper Metabolism MURR1 Domain containing 1 protein COMMD1 has been associated with copper homeostasis, NF-kappaB signaling, and sodium transport. Recently, we identified COMMD1 as a novel protein in HIF-1 signaling. Mouse embryos deficient for Commd1 have increased expression of hypoxia/HIF-regulated genes i.e. VEGF, PGK and Bnip3. Hypoxia-inducible factors (HIFs) are master regulators of oxygen homeostasis, which control angiogenesis, erythropoiesis, glycolysis and cell survival/proliferation under normal and pathologic conditions. Although HIF activity is mainly controlled by ubiquitination and protein degradation by the von Hippel Lindau (pVHL) tumor suppressor gene other mechanisms have recently been identified that regulate HIF signaling independently of pVHL.Here we characterized the mechanism by which COMMD1 regulates HIF-1alpha protein degradation. We show that COMMD1 competes with the chaperone heat shock protein HSP90beta for binding to the NH(2)-terminal DNA-binding and heterodimerization domain of HIF-1alpha to regulate HIF-1alpha stability together with HSP70. Inhibition of HSP90 activity with 17-Allylamino-17-demethoxygeldanamycin (17-AAG) increased COMMD1-mediated HIF-1alpha degradation independent of ubiquitin and pVHL.These data reveal a novel role for COMMD1 in conjunction with HSP90beta/HSP70 in the ubiquitin and O(2)-independent regulation of HIF-1alpha.

SUBMITTER: van de Sluis B

PROVIDER: S-EPMC2750754 | biostudies-other | 2009 Oct

REPOSITORIES: biostudies-other

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COMMD1 Promotes pVHL and O2-Independent Proteolysis of HIF-1alpha via HSP90/70.

van de Sluis Bart B Groot Arjan J AJ Vermeulen Jeroen J van der Wall Elsken E van Diest Paul J PJ Wijmenga Cisca C Klomp Leo W LW Vooijs Marc M

PloS one 20091005 10

<h4>Background</h4>The Copper Metabolism MURR1 Domain containing 1 protein COMMD1 has been associated with copper homeostasis, NF-kappaB signaling, and sodium transport. Recently, we identified COMMD1 as a novel protein in HIF-1 signaling. Mouse embryos deficient for Commd1 have increased expression of hypoxia/HIF-regulated genes i.e. VEGF, PGK and Bnip3. Hypoxia-inducible factors (HIFs) are master regulators of oxygen homeostasis, which control angiogenesis, erythropoiesis, glycolysis and cell ...[more]

PMID: 19802386

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Project description:BackgroundHypoxia-Inducible Factor 1 (HIF-1) is a transcription factor that is a critical mediator of the cellular response to hypoxia. Enhanced levels of HIF-1alpha, the oxygen-regulated subunit of HIF-1, is often associated with increased tumour angiogenesis, metastasis, therapeutic resistance and poor prognosis. It is in this context that we previously demonstrated that under hypoxia, bcl-2 protein promotes HIF-1/Vascular Endothelial Growth Factor (VEGF)-mediated tumour angiogenesis.Methodology/principal findingsBy using human melanoma cell lines and their stable or transient derivative bcl-2 overexpressing cells, the current study identified HIF-1alpha protein stabilization as a key regulator for the induction of HIF-1 by bcl-2 under hypoxia. We also demonstrated that bcl-2-induced accumulation of HIF-1alpha protein during hypoxia was not due to an increased gene transcription or protein synthesis. In fact, it was related to a modulation of HIF-1alpha protein expression at a post-translational level, indeed its degradation rate was faster in the control lines than in bcl-2 transfectants. The bcl-2-induced HIF-1alpha stabilization in response to low oxygen tension conditions was achieved through the impairment of ubiquitin-dependent HIF-1alpha degradation involving the molecular chaperone HSP90, but it was not dependent on the prolyl hydroxylation of HIF-1alpha protein. We also showed that bcl-2, HIF-1alpha and HSP90 proteins form a tri-complex that may contribute to enhancing the stability of the HIF-1alpha protein in bcl-2 overexpressing clones under hypoxic conditions. Finally, by using genetic and pharmacological approaches we proved that HSP90 is involved in bcl-2-dependent stabilization of HIF-1alpha protein during hypoxia, and in particular the isoform HSP90beta is the main player in this phenomenon.Conclusions/significanceWe identified the stabilization of HIF-1alpha protein as a mechanism through which bcl-2 induces the activation of HIF-1 in hypoxic tumour cells involving the beta isoform of molecular chaperone HSP90.

Dataset Information

COMMD1 Promotes pVHL and O2-Independent Proteolysis of HIF-1alpha via HSP90/70.

Publications

COMMD1 Promotes pVHL and O2-Independent Proteolysis of HIF-1alpha via HSP90/70.

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