Monalisa F Azevedo1, Constantine A Stratakis. 1. Section on Endocrinology and Genetics, Program on Developmental Endocrinology & Genetics, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, USA.
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).
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).
Authors: K Taskén; B S Skålhegg; K A Taskén; R Solberg; H K Knutsen; F O Levy; M Sandberg; S Orstavik; T Larsen; A K Johansen; T Vang; H P Schrader; N T Reinton; K M Torgersen; V Hansson; T Jahnsen Journal: Adv Second Messenger Phosphoprotein Res Date: 1997
Authors: Isabelle Bourdeau; Sonir R Antonini; André Lacroix; Lawrence S Kirschner; Ludmila Matyakhina; Dominique Lorang; Steven K Libutti; Constantine A Stratakis Journal: Oncogene Date: 2004-02-26 Impact factor: 9.867