SEPT9_v1 up-regulates hypoxia-inducible factor 1 by preventing its RACK1-mediated degradation.
A critical mediator of the cellular response to hypoxia is hypoxia-inducible factor 1 (HIF-1). Increased levels of HIF-1alpha are often associated with increased tumor metastasis, therapeutic resistance, and poorer prognosis. We recently identified a novel interaction between HIF-1alpha and the mammalian septin family member, SEPT9_v1. Septins are a highly conserved family of GTP-binding cytoskeletal proteins that are implicated in multiple cellular functions, including cell division and oncogenesis. SEPT9_v1 binds and stabilizes HIF-1alpha protein and stimulates HIF-1 transcriptional activity. SEPT9_v1-HIF-1 activation promotes tumor growth and angiogenesis. The structural and functional relationships between SEPT9_v1 and HIF-1alpha were analyzed. We found that SEPT9_v1 binds specifically with HIF-1alpha but not with HIF-2alpha. The GTPase domain of SEPT9_v1 was identified as essential for HIF-1alpha binding. A GTPase domain-derived polypeptide, corresponding to amino acids 252-379, was able to disrupt HIF-1alpha-SEPT9_v1 interaction and to inhibit HIF-1 transcriptional activity. SEPT9_v1 also protected HIF-1alpha from degradation induced by HSP90 inhibition by preventing the interaction of HIF-1alpha with the RACK1 protein, which promotes its oxygen-independent proteasomal degradation. In conclusion, a new mechanism of oxygen-independent activation of HIF-1 has been identified that is mediated by SEPT9_v1 blockade of RACK1 activity on HIF-1alpha degradation.
Amir
Sharon
S
Prostate Cancer Research Laboratory, Department of Urology, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 64239, Israel.
Wang
Ruoxiang
R
Simons
Jonathan W
JW
Mabjeesh
Nicola J
NJ
D045744:Cell Line, Tumor; D017931:DNA Primers / Q000737:chemistry; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D020558:GTP Phosphohydrolases / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D019204:GTP-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface / Q000378:metabolism*; D058112:Septins; D015854:Up-Regulation
D017931:DNA Primers; D051793:Hypoxia-Inducible Factor 1; D009363:Neoplasm Proteins; C419368:RACK1 protein, human; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface; D046988:Proteasome Endopeptidase Complex; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins; C474315:SEPTIN9 protein, human; D058112:Septins; D010100:Oxygen