Received for publication August 28, 2006.
Revised November 21, 2006.
Accepted for publication December 15, 2006.

ATP6V0C competes with pVHL in HIF-1 binding and mediates HIF-1 expression by bafilomycin A1

Abstract

HIF-1 does not only enable 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-1 and induced the p21(WAF1/Cip1)-mediated growth arrest of tumors (Lim et al, Mol Pharmacol, in press). In the present study, we addressed the mechanism underlying bafilomycin-induced HIF-1 expression. Bafilomycin stabilized HIF-1 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, the ATP6V0C expression increased HIF-1 levels in a gene dose-dependent manner. ATP6V0C competed with Von Hippel-Lindau protein in HIF-1 binding by directly interacting with HIF-1, which was stimulated by bafilomycin. In confocal images, ATP6V0C was normally present in the cytoplasm, but was translocated in company with HIF-1 to the nucleus by bafilomycin. The N-terminal end (amino acids 1-16) of HIF-1 was identified to be the ATP6V0C-interacting motif. These results suggest that ATP6V0C, a novel regulator of HIF-1, mediates HIF-1 expression by bafilomycin.

Key words: Mechanisms of cell killing/apoptosis, Angiogenesis