Distinct aerobic and hypoxic mechanisms of HIF-alpha regulation by CSN5.
Mammalian oxygen homeostasis is dependent on the HIF family of transcription factors. The CSN subunit, CSN5, binds both the CODD of HIF-1 alpha and the pVHL tumor suppressor. High CSN5 expression generates a pVHL-independent form of CSN5 that stabilizes HIF-1 alpha aerobically by inhibiting HIF-1 alpha prolyl-564 hydroxylation. Aerobic CSN5 association with HIF-1 alpha occurs independently of the CSN holocomplex, leading to HIF-1 alpha stabilization independent of Cullin 2 deneddylation. CSN5 weakly associates with HIF-1 alpha under hypoxia, but is required for optimal hypoxia-mediated HIF-1 alpha stabilization. These results indicate that CSN5 regulates aerobic as well as hypoxic HIF-1 alpha stability by different mechanisms during oncogenesis.
Bemis
Lynne
L
Departments of Medicine and Biochemistry, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
Chan
Denise A
DA
Finkielstein
Carla V
CV
Qi
Lin
L
Sutphin
Patrick D
PD
Chen
Xiaojiang
X
Stenmark
Kurt
K
Giaccia
Amato J
AJ
Zundel
Wayne
W
D000595:Amino Acid Sequence; D000075686:COP9 Signalosome Complex; D018797:Cell Cycle Proteins / Q000378:metabolism; D044842:Cullin Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology; D015180:Electrophoresis, Gel, Two-Dimensional; D006706:Homeostasis; D006801:Humans; D006900:Hydroxylation; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes; D010100:Oxygen / Q000378:metabolism*; D010447:Peptide Hydrolases; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D011487:Protein Conformation; D011506:Proteins / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism* / Q000502:physiology; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein
C466088:COPS7A protein, human; C105153:CUL2 protein, human; D018797:Cell Cycle Proteins; D044842:Cullin Proteins; D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D011506:Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D010447:Peptide Hydrolases; C501488:COPS5 protein, human; D000075686:COP9 Signalosome Complex; C497446:VHL protein, human; D010100:Oxygen