title: cAMP signaling in cortisol-producing adrenal adenoma.
abstract: The cAMP signaling pathway is one of the major players in the regulation of growth and hormonal secretion in adrenocortical cells. Although its role in the pathogenesis of adrenocortical hyperplasia associated with Cushing's syndrome has been clarified, a clear involvement of the cAMP signaling pathway and of one of its major downstream effectors, the protein kinase A (PKA), in sporadic adrenocortical adenomas remained elusive until recently. During the last year, a report by our group and three additional independent groups showed that somatic mutations of PRKACA, the gene coding for the catalytic subunit α of PKA, are a common genetic alteration in patients with Cushing's syndrome due to adrenal adenomas, occurring in 35-65% of the patients. In vitro studies revealed that those mutations are able to disrupt the association between catalytic and regulatory subunits of PKA, leading to a cAMP-independent activity of the enzyme. Despite somatic PRKACA mutations being a common finding in patients with clinically manifest Cushing's syndrome, the pathogenesis of adrenocortical adenomas associated with subclinical hypercortisolism seems to rely on a different molecular background. In this review, the role of cAMP/PKA signaling in the regulation of adrenocortical cell function and its alterations in cortisol-producing adrenocortical adenomas will be summarized, with particular focus on recent developments.
authors.affiliation: Institute of Pharmacology and ToxicologyUniversity of Würzburg, Versbacher Str. 9, 97078 Würzburg, GermanyRudolf Virchow CenterJosef-Schneider-Str. 2, 97080 Würzburg, GermanyMedizinische Klinik und Poliklinik IVLudwig-Maximilians-Universität München, Ziemssenstraβe 1, 80336 München, GermanyDepartment of Medicine IEndocrine and Diabetes Unit, University Hospital, University of Würzburg, Oberdürrbacher Str. 6, 97080 Würzburg, GermanyComprehensive Cancer Center MainfrankenUniversity of Würzburg, Josef-Schneider-Str. 6, 97080 Würzburg, Germany Institute of Pharmacology and ToxicologyUniversity of Würzburg, Versbacher Str. 9, 97078 Würzburg, GermanyRudolf Virchow CenterJosef-Schneider-Str. 2, 97080 Würzburg, GermanyMedizinische Klinik und Poliklinik IVLudwig-Maximilians-Universität München, Ziemssenstraβe 1, 80336 München, GermanyDepartment of Medicine IEndocrine and Diabetes Unit, University Hospital, University of Würzburg, Oberdürrbacher Str. 6, 97080 Würzburg, GermanyComprehensive Cancer Center MainfrankenUniversity of Würzburg, Josef-Schneider-Str. 6, 97080 Würzburg, Germany davide.calebiro@toxi.uni-wuerzburg.de.
authors.forename: Davide
authors.initials: D
authors.lastname: Calebiro
authors.affiliation: Institute of Pharmacology and ToxicologyUniversity of Würzburg, Versbacher Str. 9, 97078 Würzburg, GermanyRudolf Virchow CenterJosef-Schneider-Str. 2, 97080 Würzburg, GermanyMedizinische Klinik und Poliklinik IVLudwig-Maximilians-Universität München, Ziemssenstraβe 1, 80336 München, GermanyDepartment of Medicine IEndocrine and Diabetes Unit, University Hospital, University of Würzburg, Oberdürrbacher Str. 6, 97080 Würzburg, GermanyComprehensive Cancer Center MainfrankenUniversity of Würzburg, Josef-Schneider-Str. 6, 97080 Würzburg, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Di Dalmazi
authors.affiliation: Institute of Pharmacology and ToxicologyUniversity of Würzburg, Versbacher Str. 9, 97078 Würzburg, GermanyRudolf Virchow CenterJosef-Schneider-Str. 2, 97080 Würzburg, GermanyMedizinische Klinik und Poliklinik IVLudwig-Maximilians-Universität München, Ziemssenstraβe 1, 80336 München, GermanyDepartment of Medicine IEndocrine and Diabetes Unit, University Hospital, University of Würzburg, Oberdürrbacher Str. 6, 97080 Würzburg, GermanyComprehensive Cancer Center MainfrankenUniversity of Würzburg, Josef-Schneider-Str. 6, 97080 Würzburg, Germany Institute of Pharmacology and ToxicologyUniversity of Würzburg, Versbacher Str. 9, 97078 Würzburg, GermanyRudolf Virchow CenterJosef-Schneider-Str. 2, 97080 Würzburg, GermanyMedizinische Klinik und Poliklinik IVLudwig-Maximilians-Universität München, Ziemssenstraβe 1, 80336 München, GermanyDepartment of Medicine IEndocrine and Diabetes Unit, University Hospital, University of Würzburg, Oberdürrbacher Str. 6, 97080 Würzburg, GermanyComprehensive Cancer Center MainfrankenUniversity of Würzburg, Josef-Schneider-Str. 6, 97080 Würzburg, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Bathon
authors.affiliation: Institute of Pharmacology and ToxicologyUniversity of Würzburg, Versbacher Str. 9, 97078 Würzburg, GermanyRudolf Virchow CenterJosef-Schneider-Str. 2, 97080 Würzburg, GermanyMedizinische Klinik und Poliklinik IVLudwig-Maximilians-Universität München, Ziemssenstraβe 1, 80336 München, GermanyDepartment of Medicine IEndocrine and Diabetes Unit, University Hospital, University of Würzburg, Oberdürrbacher Str. 6, 97080 Würzburg, GermanyComprehensive Cancer Center MainfrankenUniversity of Würzburg, Josef-Schneider-Str. 6, 97080 Würzburg, Germany Institute of Pharmacology and ToxicologyUniversity of Würzburg, Versbacher Str. 9, 97078 Würzburg, GermanyRudolf Virchow CenterJosef-Schneider-Str. 2, 97080 Würzburg, GermanyMedizinische Klinik und Poliklinik IVLudwig-Maximilians-Universität München, Ziemssenstraβe 1, 80336 München, GermanyDepartment of Medicine IEndocrine and Diabetes Unit, University Hospital, University of Würzburg, Oberdürrbacher Str. 6, 97080 Würzburg, GermanyComprehensive Cancer Center MainfrankenUniversity of Würzburg, Josef-Schneider-Str. 6, 97080 Würzburg, Germany.
authors.forename: Cristina L
authors.initials: CL
authors.lastname: Ronchi
authors.affiliation: Institute of Pharmacology and ToxicologyUniversity of Würzburg, Versbacher Str. 9, 97078 Würzburg, GermanyRudolf Virchow CenterJosef-Schneider-Str. 2, 97080 Würzburg, GermanyMedizinische Klinik und Poliklinik IVLudwig-Maximilians-Universität München, Ziemssenstraβe 1, 80336 München, GermanyDepartment of Medicine IEndocrine and Diabetes Unit, University Hospital, University of Würzburg, Oberdürrbacher Str. 6, 97080 Würzburg, GermanyComprehensive Cancer Center MainfrankenUniversity of Würzburg, Josef-Schneider-Str. 6, 97080 Würzburg, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Beuschlein
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000235:genetics / Q000378:metabolism*; D018246:Adrenocortical Adenoma / Q000235:genetics / Q000378:metabolism*; D003480:Cushing Syndrome / Q000235:genetics / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism*; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D009154:Mutation; D015398:Signal Transduction
chemical_list: D000242:Cyclic AMP; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits; C517757:PRKACA protein, human; D006854:Hydrocortisone