title: Phosphodiesterase 11A expression in the adrenal cortex, primary pigmented nodular adrenocortical disease, and other corticotropin-independent lesions.
abstract: A variety of adrenal tumors and bilateral adrenocortical hyperplasias (BAH) leading to Cushing syndrome (CS) may be caused by aberrant cAMP signaling. We recently identified patients with a micronodular form of BAH that we have called "isolated micronodular adrenocortical disease" (iMAD) in whom CS was associated with inactivating mutations in phosphodiesterase (PDE) 11A ( PDE11A). In the present study, we examined PDE11A expression in normal adrenocortical tissue, sporadic tumors, and hyperplasias without PDE11A mutations, and primary pigmented nodular adrenocortical disease (PPNAD) and adenomas from patients with PRKAR1A and a single tumor with a GNAS mutation. The total number of the tumor samples that we studied was 22. Normal human tissues showed consistent PDE11A expression. There was variable expression of PDE11A in sporadic adrenocortical hyperplasia or adenomas; PPNAD tissues from patients with PRKAR1A mutations expressed consistently high levels of PDE11A in contrast to adenomas caused by GNAS mutations. Phosphorylated CREB was the highest in tissues from patients with iMAD compared to all other forms of BAH and normal adrenal tissue. We conclude that PDE11A is expressed widely in adrenal cortex. Its expression appears to be increased in PPNAD but varies widely among other adrenocortical tumors. PRKAR1A expression appears to be higher in tissues with PDE11A defects. Finally, sequencing defects in PDE11A are associated with a high state of CREB phosphorylation, just like PRKAR1A mutations. These preliminary data suggest that these two molecules are perhaps regulated in a reverse manner in their control of cAMP signaling in adrenocortical tissues.
authors.affiliation: Section on Endocrinology & Genetics, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Boikos
authors.forename: A
authors.initials: A
authors.lastname: Horvath
authors.forename: S
authors.initials: S
authors.lastname: Heyerdahl
authors.forename: E
authors.initials: E
authors.lastname: Stein
authors.forename: A
authors.initials: A
authors.lastname: Robinson-White
authors.forename: I
authors.initials: I
authors.lastname: Bossis
authors.forename: J
authors.initials: J
authors.lastname: Bertherat
authors.forename: J A
authors.initials: JA
authors.lastname: Carney
authors.forename: C A
authors.initials: CA
authors.lastname: Stratakis
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000302:Adrenal Cortex / Q000378:metabolism* / Q000473:pathology; D000307:Adrenal Gland Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D009154:Mutation; D010727:Phosphoric Diester Hydrolases / Q000096:biosynthesis* / Q000235:genetics; D010766:Phosphorylation; D015398:Signal Transduction / Q000235:genetics
chemical_list: C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; C406737:PDE11A protein, human