H. Suzuki et al., Dephosphorylated hypoxia-inducible factor 1 alpha as a mediator of p53-dependent apoptosis during hypoxia, ONCOGENE, 20(41), 2001, pp. 5779-5788
Under hypoxia, HIF-1 alpha binds to aryl hydrocarbon receptor nuclear trans
locator (ARNT, also called HIF-1 alpha) to activate expression of genes imp
ortant for cell survival. Alternatively, HIF-1 alpha can bind to the tumor
suppressor p53 and promote p53-dependent apoptosis. Here we show that the o
pposite functions of HIF-1 alpha are distinguished by its phosphorylation s
tatus. Two distinguishable forms of HIF-1 alpha, phosphorylated and dephosp
horylated, were induced during hypoxia-induced apoptosis. The phosphorylate
d HIF-1 alpha was the major form that bound to ARNT. Ectopically expressed
ARNT was consistently able to enhance HIF-1 alpha phosphorylation in a bind
ing-dependent manner. In contrast, the dephosphorylated HIF-1 alpha was the
major form that bound to p53. Depletion of the dephosphorylated HIF-1 alph
a, by using the Hsp90 inhibitor geldanamycin A that had little effect on th
e phosphorylated HIF-1 alpha expression, suppressed p53 induction and subse
quent apoptosis. Depletion of dephosphorylated HIF-1 alpha also prevented h
ypoxia-induced nuclear accumulation of HDM2, a negative regulator of p53. O
ur results indicate that the functions of HIF-1 alpha varied with its phosp
horylation status and that dephosphorylated HIF-1 alpha mediated apoptosis
by binding to and stabilizing p53.