Zinc induces the accumulation of hypoxia-inducible factor (HIF)-1alpha, but inhibits the nuclear translocation of HIF-1beta, causing HIF-1 inactivation.

The replacement of heme iron by cobalt or nickel in a putative oxygen sensor is supposed to reduce oxygen binding to the heme protein, resulting in HIF-1 activation and erythropoietin (EPO) induction. According to this hypothesis, zinc might be another example of a transition metal which is capable of stimulating EPO production. By substituting for heme iron, zinc protoporphyrin IX is produced, which has a known low oxygen affinity. However, it has been reported that zinc fails to induce EPO in normoxia, and that it suppresses EPO production in hypoxic cells. This unexpected effect of zinc on EPO production is not understood. In this study, we found that zinc induced the accumulation and nuclear translocation of hypoxia-inducible factor (HIF)-1alpha but inhibited the nuclear translocation of HIF-1beta, which inactivated HIF-1 and suppressed EPO mRNA induction in hypoxic cells.