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Phorbol Ester Stimulates the Nonhypoxic Induction of a Novel Hypoxia-Inducible Factor 1 Isoform

Implications for Tumor Promotion

¹ Human Genome Research Institute and Cancer Research Institute and
² Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea, and
³ Laboratory of Human Carcinogenesis, National Cancer Institute, NIH, Bethesda, Maryland

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-1ß 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-1⁷⁸⁵) without altering the reading frame and therefore the COOH-terminal transcriptional activity. HIF-1⁷⁸⁵ is induced markedly by PMA and heat shock, the latter of which is also known to induce HIF-1. HIF-1⁷⁸⁵ escapes from lysine acetylation because of the loss of Lys⁵³² 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-1⁷⁸⁵ overexpression strikingly enhanced tumor growth in vivo. These results suggest that HIF-1⁷⁸⁵ 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.

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