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


RESULTS
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.


CONCLUSIONS
These data reveal a novel role for COMMD1 in conjunction with HSP90beta/HSP70 in the ubiquitin and O(2)-independent regulation of HIF-1alpha.
Complex Genetics Section, DBG-Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
Bart
B
van de Sluis
Arjan J
AJ
Groot
Jeroen
J
Vermeulen
Elsken
E
van der Wall
Paul J
PJ
van Diest
Cisca
C
Wijmenga
Leo W
LW
Klomp
Marc
M
Vooijs
D048868:Adaptor Proteins, Signal Transducing; D016227:Benzoquinones / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D005786:Gene Expression Regulation; D016147:Genes, Tumor Suppressor; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D015398:Signal Transduction; D025801:Ubiquitin / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D016227:Benzoquinones; C480519:COMMD1 protein, human; D002352:Carrier Proteins; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047029:Lactams, Macrocyclic; D025801:Ubiquitin; C112765:tanespimycin; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D046988:Proteasome Endopeptidase Complex; D010100:Oxygen