Phorbol Ester Stimulates the Nonhypoxic Induction of a Novel Hypoxia-Inducible Factor 1 Isoform: Implications for Tumor Promotion

Hypoxia-inducible factor-1 (HIF-1), which is present at higher levels in human tumors, plays important roles in tumor promotion. It is composed of HIF-1 and HIF-1 subunits and its activity depends on the amount of HIF-1 , which is tightly controlled by cellular oxygen tension. In addition to hypoxia, various nonhypoxic stimuli can stabilize HIF-1 in tumor cells, implying that both hypoxic and nonhypoxic stimuli contribute to the overexpression of HIF-1 in tumors. On the other hand, phorbol esters such as phorbol-12-myristate-13-acetate (PMA) are known to be potent tumor promoters. Here, we identified a novel HIF-1 isoform, which is regulated primarily by PMA. The variant mRNA lacks exon 11 and produces a 785-amino acid isoform (HIF-1 ) without altering the reading frame and therefore the COOH-terminal transcriptional activity. HIF-1 785 is induced markedly by PMA and heat shock, the latter of which is also known to induce HIF-1 . HIF-1 785 escapes from lysine acetylation because of the loss of Lys and was stabilized under normoxic conditions. Its expression was blocked by reducing agents and by a mitogen-activated protein/extracellular signal-regulated kinase-1 inhibitor and enhanced by hydrogen peroxide. In addition, HIF-1 785 overexpression strikingly enhanced tumor growth in vivo. These results suggest that HIF-1 785 is induced by PMA under normoxic conditions via a redox-dependent mitogen-activated protein/extracellular signal-regulated kinase-1 pathway and that it plays an important role in tumor promotion.