The transcriptome that mediates increased cyclic adenosine monophosphate signaling in PRKAR1A defects and other settings

Abstract

Objective: To review current knowledge on the involvement of cyclic adenosine monophosphate (cAMP) and interacting signaling pathways in predisposition to tumor formation in primary pigmented nodular adrenocortical disease (PPNAD), a type of bilateral adrenal hyperplasia (BAH) related to the multiple endocrine neoplasia Carney complex, and also in isolated PPNAD and other BAHs.

Methods: We review the pertinent literature and discuss genetic defects associated with various endocrine and nonendocrine tumors.

Results: A decade ago, we discovered that PPNAD and the Carney complex are caused by PRKAR1A mutations. PRKAR1A encodes the protein kinase A (PKA) regulatory subunit type IA, an important regulator of cAMP signaling in most cells. Recently, we described PKA or PRKAR1A abnormalities in a variety of other BAHs; in some of these cases, mutations in additional genes of the cAMP signaling pathway, the phosphodiesterases, were identified. Transcriptomic analyses of human lesions or animal models showed that abnormal cAMP/PKA signaling in the adrenal glands, and also in other tissues such as bone, leads to proliferation of tissue-specific pluripotential cells through activation of Wnt signaling.

Conclusion: Recent findings indicate the relevance of cAMP signaling in the pathogenesis of adrenocortical disease and point to the Wnt signaling pathway as a potential important mediator of tumorigenesis related to increased cAMP or PKA signaling (or both).

Figure 1

The cyclic adenosine monophosphate (cAMP) signaling pathway and its genetic defects causing endocrine diseases. ATP = adeno-sine triphosphate; C = catalytic subunit of PKA; CNC = Carney complex; GDP = guanosine diphosphate; GTP = guanosine triphosphate; MAS = McCune-Albright syndrome; PDE = phosphodiesterase; PKA = protein kinase A; R = regulatory subunit of PKA; a, b, g = subunits of G protein.