Phorbol ester stimulates the nonhypoxic induction of a novel hypoxia-inducible factor 1alpha 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-1alpha and HIF-1beta subunits and its activity depends on the amount of HIF-1alpha, which is tightly controlled by cellular oxygen tension. In addition to hypoxia, various nonhypoxic stimuli can stabilize HIF-1alpha in tumor cells, implying that both hypoxic and nonhypoxic stimuli contribute to the overexpression of HIF-1alpha 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-1alpha isoform, which is regulated primarily by PMA. The variant mRNA lacks exon 11 and produces a 785-amino acid isoform (HIF-1alpha(785)) without altering the reading frame and therefore the COOH-terminal transcriptional activity. HIF-1alpha(785) is induced markedly by PMA and heat shock, the latter of which is also known to induce HIF-1alpha. HIF-1alpha(785) escapes from lysine acetylation because of the loss of Lys(532) 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-1alpha(785) overexpression strikingly enhanced tumor growth in vivo. These results suggest that HIF-1alpha(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.
Chun
Yang-Sook
YS
Human Genome Research Institute and Cancer Research Institute, National Cancer Institute, NIH, Bethesda, Maryland, USA.
Lee
Kyoung-Hwa
KH
Choi
Eunjoo
E
Bae
Soo-Young
SY
Yeo
Eun-Jin
EJ
Huang
L Eric
LE
Kim
Myung-Suk
MS
Park
Jong-Wan
JW
D017398:Alternative Splicing; D000818:Animals; D002273:Carcinogens / Q000494:pharmacology*; D002455:Cell Division / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D019175:DNA Methylation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051379:Mice; D008819:Mice, Nude; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D015533:Transcriptional Activation; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects
D002273:Carcinogens; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020033:Protein Isoforms; D012333:RNA, Messenger; D014157:Transcription Factors; D013755:Tetradecanoylphorbol Acetate