SEPT9_i1 is required for the association between HIF-1α and importin-α to promote efficient nuclear translocation.
Septin 9 isoform 1 (SEPT9_i1) protein associates with hypoxia-inducible factor (HIF)-1α to augment HIF-1 transcriptional activity. The first 25 amino acids of SEPT9_i1 (N 25) are unique compared with other members of the mammalian septin family. This N 25 domain is critical for HIF-1 activation by SEPT9_i1 but not essential for the protein-protein interaction. Here, we show that expression of N 25 induces a significant dose-dependent inhibition of HIF-1 transcriptional activity under normoxia and hypoxia without influencing cellular HIF-1α protein levels. In vivo, N 25 expression inhibits proliferation, tumor growth and angiogenesis concomitant with decreased expression levels of intratumoral HIF-1 downstream genes. Depletion of endogenous SEPT9_i1 or the exogenous expression of N 25 fragment reduces nuclear HIF-1α levels accompanied by reciprocal accumulation of HIF-1α in the cytoplasm. Mechanistically, SEPT9_i1 binds to importin-α through N 25 depending on its bipartite nuclear localization signal, to scaffold the association between HIF-1α and importin-α, which leads to facilitating HIF-1α nuclear translocation. Our data explore a new and a previously unrecognized role of a septin protein in the cytoplasmic-nuclear translocation process. This new level in the regulation of HIF-1α translocation is critical for efficient HIF-1 transcriptional activation that could be targeted for cancer therapeutics.
Prostate Cancer Research Laboratory, Department of Urology, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Maya
M
Golan
Nicola J
NJ
Mabjeesh
D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D000818:Animals; D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D058112:Septins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D028901:alpha Karyopherins / Q000235:genetics* / Q000378:metabolism
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020033:Protein Isoforms; D028901:alpha Karyopherins; D049452:Green Fluorescent Proteins; C474315:SEPTIN9 protein, human; D058112:Septins
HIF-1α; SEPT9_i1; importin-α; nuclear translocation