RT Journal Article
SR Electronic
T1 ATP6V0C Competes with Von Hippel-Lindau Protein in Hypoxia-Inducible Factor 1α (HIF-1α) Binding and Mediates HIF-1α Expression by Bafilomycin A1
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 942
OP 948
DO 10.1124/mol.106.030296
VO 71
IS 3
A1 Ji-Hong Lim
A1 Jong-Wan Park
A1 Sung Joon Kim
A1 Myung-Suk Kim
A1 Sang-Ki Park
A1 Randall S. Johnson
A1 Yang-Sook Chun
YR 2007
UL http://molpharm.aspetjournals.org/content/71/3/942.abstract
AB HIF-1α not only enables cells to survive under hypoxic conditions but also promotes cell cycle arrest and apoptosis. Therefore, its expression should be controlled at optimal levels in growing tumors. We recently reported that bafilomycin A1 exorbitantly expressed HIF-1α and induced the p21WAF1/Cip1-mediated growth arrest of tumors (Mol Pharmacol70:1856–1865, 2006). In the present study, we addressed the mechanism underlying bafilomycin-induced HIF-1α expression. Bafilomycin stabilized HIF-1α under normoxic conditions without changes in intracellular pH. However, when ATP6V0C, the target protein of bafilomycin, was knocked down, this bafilomycin effect was significantly attenuated. Inversely, ATP6V0C expression increased HIF-1α levels in a gene dose-dependent manner. ATP6V0C competed with Von Hippel-Lindau protein in HIF-1α binding by directly interacting with HIF-1α, which was stimulated by bafilomycin. In confocal images, ATP6V0C was normally present in the cytoplasm but was translocated in company with HIF-1α to the nucleus by bafilomycin. The N-terminal end (amino acids 1–16) of HIF-1α was identified as the ATP6V0C-interacting motif. These results suggest that ATP6V0C, a novel regulator of HIF-1α, mediates HIF-1α expression by bafilomycin. The American Society for Pharmacology and Experimental Therapeutics