Abstract
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 PKA subunit expression have been identified in inherited and sporadic endocrine tumors, but are rare indicating the presence of nongenomic pathological PKA activation. In the present study, we examined the impact of hypoxia on PKA activation using human growth hormone (GH)-secreting pituitary tumors as a model of an endocrine disease displaying PKA-CREB overactivation. We show that hypoxia activates PKA 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 PKA 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 PKA 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 PKA pathway may be more efficiently targeted.
Highlights
hypoxia inducible factors (HIFs)-1α is overexpressed in growth hormone (GH)-secreting pituitary tumors
Immunohistochemistry performed on archival paraffin embedded GH-secreting pituitary tumors from patients with acromegaly and normal autoptic pituitary samples showed abundant nuclear HIF-1α staining in acromegalic tumors and virtually absent staining in the normal pituitary (Fig. 1a)
Hypoxia has long been recognized as a contributing factor to the development and survival of tumor cells [53], and HIF-1α has been identified as a key mediator of the adaptive processes which confer a survival advantage in the hypoxic tumor microenvironment [21, 22, 54]
Summary
Division of Molecular Genetics, Deutsches Krebsforschungszentrum, Heidelberg, Germany. Present address: Division of Molecular Genetics, Deutsches Krebsforschungszentrum, Heidelberg, Germany. The PKA tetrameric holoenzyme is composed of regulatory (R) and catalytic (C) subunit dimers. The regulatory subunits are each present in alpha (α) and beta (β) isoforms (RIα, RIIα, RIβ, and RIIβ) and their expression and tissue-specific balance are essential in shaping the specificity and degree of its activity [1, 2]. Following the binding of the second messenger 3′5′-cyclic adenosine monophosphate (cAMP) to the regulatory subunit dimer, a conformational change occurs which allows the active catalytic subunit to dissociate and phosphorylate serine/threonine residues of substrate proteins, like cAMP-responsive element (CRE) binding protein (CREB) [3,4,5]. PKA is deregulated in several human cancers and in particular in endocrine tumors such as thyroid cancer, adrenal tumors (Cushing’s syndrome, Carney complex), and GH-secreting pituitary tumors (acromegaly) as a result of altered expression of its subunits [6,7,8]
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