A new HIF-1 alpha variant induced by zinc ion suppresses HIF-1-mediated hypoxic responses

The expressions of hypoxia-inducible genes are upregulated by hypoxia-induc ible factor 1 (RIF-1), which is a heterodimer of HIF-1 alpha and HIF-1 beta /ARNT (aryl hydrocarbon receptor nuclear transporter). Under hypoxic condi tions, HIF-1 alpha becomes stabilized and both HIF-1 alpha and ARNT are tra nslocated into the nucleus and codimerized, binding to the HIF-1 consensus sequence and transactivating hypoxia-inducible genes. Other than hypoxia, c obalt and nickel, which can substitute for iron in the ferroprotein, induce the stabilization of HIF-1 alpha and the activation of HIF-1. We found pre viously that, although zinc, another example of a metal substitute for iron , stabilized HIF-1 alpha, it suppressed the formation of HIF-1 by blocking the nuclear translocation of ARNT. Here, we identify a new spliced variant of human HIF-1 alpha that is induced by zinc. The isoform lacks the 12th ex on, which produced a frame-shift and gave a shorter form of HIF-1 alpha (55 7 amino acids), designated HIF-1 alphaZ (HIF-1 induced by Zn). This moiety was found to inhibit HIF-1 activity and reduce mRNA expressions of the hypo xia-inducible genes. It blocked the nuclear translocation of ARNT but not t hat of endogenous HIF-1 alpha, and was associated with ARNT in the cytosol. These results suggest that HIF-1 alphaZ functions as a dominant-negative i soform of HIF-1 by sequestering ARNT in the cytosol. In addition, the gener ation of HIF-1 alphaZ seems to be responsible for the inhibitory effects of the zinc ion on HTF-1-mediated hypoxic responses, because the expressed HI F-1 alphaZ behaved in the same manner as zinc in terms of inhibited HIF-1 a ctivity and ARNT translocation.