Cyclic AMP represses the hypoxic induction of hypoxia-inducible factors in PC12 cells.
Hypoxia-inducible factor 1 (HIF-1) is a master regulator for hypoxic activation of genes for angiogenesis, hormone synthesis, glycolysis and cell survival. In addition to hypoxic stimulus, various effectors and reagents were reported to affect HIF-1 activity. Here, we show that cyclic AMP (cAMP) down-regulates the HIF-1 activity in pheochromocytoma PC12 cells but not in Hep3B and HeLa cells. Hypoxia response element-dependent reporter activity was decreased by the addition of dibutyryl cAMP. Expression of protein kinase A (PKA) catalytic alpha-subunits repressed the HIF-1 activity. HIF-1alpha and HLF (HIF-2alpha or EPAS1) protein levels were decreased by the treatment with dibutyryl cAMP. Although CREB was served as a negative factor for the HIF-1 activity, it may not be a major PKA target in the cAMP-dependent HIF-alpha repression pathway. Induction of hypoxia responsive genes was suppressed by dibutyryl cAMP. Our results provide additional insight into a regulatory mechanism of hypoxic response.
Torii
Satoru
S
Department of Biomolecular Sciences, Graduate School of Life Sciences, Tohoku University, Japan.
Okamura
Norikazu
N
Suzuki
Yohei
Y
Ishizawa
Toshiyuki
T
Yasumoto
Ken-Ichi
K
Sogawa
Kazuhiro
K
D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism; D015153:Blotting, Western; D050882:CREB-Binding Protein / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D015536:Down-Regulation; D006367:HeLa Cells; D006801:Humans; D000860:Hypoxia; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism*; D016716:PC12 Cells; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction
D050976:Basic-Leucine Zipper Transcription Factors; D051793:Hypoxia-Inducible Factor 1; D000242:Cyclic AMP; D050882:CREB-Binding Protein; D017868:Cyclic AMP-Dependent Protein Kinases