2010;53:215C222. are important second messengers in signaling, involved in cell proliferation, cell-cycle regulation, and metabolic function. Intracellular cAMP and cGMP levels are controlled both at their production, by activated adenylyl-cyclase and guanylyl-cyclase, which catalyze conversion of ATP and GTP to cAMP and cGMP, respectively, and at their destruction, by cyclic nucleotide phosphodiesterases (PDEs) [1] (Physique 1). Open in a separate window Physique 1 Summary c-Fms-IN-10 of cyclic nucleotide signaling pathways: cyclic nucleotides are generated by adenylyl-cyclase and guanylyl-cyclase; the former, activated by G-protein-coupled receptors, and the latter, by molecules such as natriuretic peptide or nitric oxide. In turn, cAMP activates PKA and EPAC. EPAC is usually involved in the regulation of several cellular processes, including integrin-mediated cell adhesion and cellCcell junction formation [74], exocytosis [75,76,77], and insulin secretion, while PKA is usually involved in metabolic processes, cell growth, differentiation, and proliferation. cGMP activates PKG which in turn mediates the phosphorylation of proteins involved in apoptosis, inflammation, and other physiologic processes, c-Fms-IN-10 including smooth muscle contractility [78], the visual transduction cascade, and platelet aggregation. By catalyzing hydrolysis of cAMP and cGMP, c-Fms-IN-10 PDEs regulate their intracellular concentrations and, consequently, their myriad biological effects. Phosphodiesterases are enzymes that catalyze the hydrolysis of the 3 cyclic phosphate bond of cyclic nucleotides. To date, 11 PDE gene families have been identified, based on their amino acid sequences, biochemical properties, and inhibitor profiles. Different PDEs can share the same catalytic function, but may differ in tissue expression and intracellular localization (Table 1) [2]. Table 1 Summary of human phosphodiesterases: their substrate, tissue expression, subcellular location and inhibitors. is located on chromosome 17q22C24, and more than a hundred different mutations of this gene have been described [13,15?,16C19]. Altered cAMP signaling, somatic mutations, and somatic losses in the 17q22C24 locus have all been reported in adrenocortical adenomas and CYFIP1 adrenocortical cancer. Specifically, 17q22C24 losses were found in 23% and 53% of adrenocortical adenomas and adrenocortical cancer samples, respectively. Both cancers and adenomas with 17q losses had higher PKA activity in response to cAMP when compared to comparable tumors without 17q losses [20?]. A third link between cAMP and tumorigenesis is usually through altered PDEs. Inactivating molecular defects in PDEs lead to high cAMP or cGMP levels that in turn generate a continuous activation of the c-Fms-IN-10 cAMP/PKA cascade. In 2006, our laboratory identified five mutations in a group of 16 patients with adrenocortical hyperplasia. Three of these mutations led to premature terminations with truncated proteins, and the other two were missense mutations (R804H and R867G), leading to defective proteins [21??]. Although germline truncating-protein mutations are seen in the general population, they are significantly more common among patients with adrenal hyperplasia [22]. Somatic missense mutations are frequently found in adrenocortical tumors: adrenocortical cancer (ACA), adrenocortical adenomas, and corticotrophin (ACTH)-impartial macronodular adrenal hyperplasia or AIMAH. In line with the above, higher cAMP levels and lower PDE11A expression were observed in AIMAH and ACA tissues studied by immunohistochemistry [23?]. Interestingly, a higher frequency of variants has been found in patients with mutations, suggesting a contribution of PDE11A to adrenal and testicular tumor formation in CNC [24?]. More recently, genetic defects were found to be significantly increased in prostatic cancer patients, compared with healthy controls, suggesting that genetic variants may play a role in susceptibility to prostatic cancer, as well [25??]. A second PDE found to be involved in adrenocortical tumor predisposition was missense mutation (p.H305P) was then described in a young lady with isolated micronodular adrenocortical disease. Functional studies showed high levels of cAMP in HEK293 cells transfected with the mutant gene [26]. Subsequently, additional three novel mutations in were described in patients with adrenal tumors [27]. PDE8 is usually.