PT  - JOURNAL ARTICLE
AU  - Ji-Hong Lim
AU  - Jong-Wan Park
AU  - Sung Joon Kim
AU  - Myung-Suk Kim
AU  - Sang-Ki Park
AU  - Randall S. Johnson
AU  - Yang-Sook Chun
TI  - ATP6V0C Competes with Von Hippel-Lindau Protein in Hypoxia-Inducible Factor 1α (HIF-1α) Binding and Mediates HIF-1α Expression by Bafilomycin A1
AID  - 10.1124/mol.106.030296
DP  - 2007 Mar 01
TA  - Molecular Pharmacology
PG  - 942--948
VI  - 71
IP  - 3
4099  - http://molpharm.aspetjournals.org/content/71/3/942.short
4100  - http://molpharm.aspetjournals.org/content/71/3/942.full
SO  - Mol Pharmacol2007 Mar 01; 71
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