title: Control of HIF-1alpha expression by eIF2 alpha phosphorylation-mediated translational repression.
abstract: Hypoxia inducible factor 1alpha (HIF-1alpha) plays a central role in regulating tumor angiogenesis via its effects on vascular endothelial growth factor (VEGF) transcription, and its expression is regulated through proteasome-mediated degradation. Paradoxically, previous studies have shown that proteasome inhibitors (PI) block tumor angiogensis by reducing VEGF expression, but the mechanisms have not been identified. Here, we report that PIs down-regulated HIF-1alpha protein levels and blocked HIF-1alpha transcriptional activity in human prostate cancer cells. PIs induced phosphorylation of the translation initiation factor 2alpha (eIF2alpha), which caused general translational repression to inhibit HIF-1alpha expression. Furthermore, PIs induced HIF-1alpha accumulation in LNCaP-Pro5 cells depleted of eIF2alpha via siRNA transfection and in MEFs expressing a phosphorylation-deficient mutant form of eIF2alpha. Finally, PIs failed to induce eIF2alpha phosphorylation or translational attenuation in DU145 or 253JB-V cells, and, in these cells, PIs promoted HIF-1alpha accumulation. Our data established that PIs down-regulated HIF-1alpha expression in cells that display activation of the unfolded protein response by stimulating phosphorylation of eIF2alpha and inhibiting HIF-1alpha translation.
authors.affiliation: Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Keyi
authors.initials: K
authors.lastname: Zhu
authors.forename: Waikin
authors.initials: W
authors.lastname: Chan
authors.forename: John
authors.initials: J
authors.lastname: Heymach
authors.forename: Miles
authors.initials: M
authors.lastname: Wilkinson
authors.forename: David J
authors.initials: DJ
authors.lastname: McConkey
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D045744:Cell Line, Tumor; D015536:Down-Regulation; D015852:Eukaryotic Initiation Factor-2 / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D007783:Lactones / Q000494:pharmacology; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D061988:Proteasome Inhibitors; D014176:Protein Biosynthesis; D011719:Pyrazines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D001897:Boronic Acids; D000069286:Bortezomib; D015852:Eukaryotic Initiation Factor-2; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007783:Lactones; D046988:Proteasome Endopeptidase Complex; D061988:Proteasome Inhibitors; D011719:Pyrazines; D011758:Pyrroles; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C475865:marizomib