Hypoxia and the hypoxia inducible factor 1α activate protein kinase A by repressing RII beta subunit transcription.

Overactivation of the cAMP signal transduction pathway plays a central role in the pathogenesis of endocrine tumors. Genetic aberrations leading to increased intracellular cAMP or directly affecting subunit expression have been identified in inherited and sporadic endocrine tumors, but are rare indicating the presence of nongenomic pathological duanyu1529 activation. In the present study, we examined the impact of hypoxia on duanyu1529 activation using human growth hormone (GH)-secreting pituitary tumors as a model of an endocrine disease displaying overactivation. We show that hypoxia activates duanyu1529 and enhances CREB transcriptional activity and subsequently GH oversecretion. This is due to a previously uncharacterized ability of HIF-1α to suppress the transcription of the duanyu1529 regulatory subunit 2B (PRKAR2B) by sequestering Sp1 from the PRKAR2B promoter. The present study reveals a novel mechanism through which the transcription factor HIF-1α transduces environmental signals directly onto duanyu1529 activity, without affecting intracellular cAMP concentrations. By identifying a point of interaction between the cellular microenvironment and intracellular enzyme activation, neoplastic, and nonneoplastic diseases involving overactivated duanyu1529 pathway may be more efficiently targeted.

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