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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.