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.

Key words

adrenal tumors - Cushing syndrome - protein kinase A - cyclic AMP - phosphodiesterases

References

• 1 Stratakis CA, Boikos SA. Genetics of adrenal tumors associated with Cushing's syndrome: a new classification for bilateral adrenocortical hyperplasias.  Nat Clin Pract Endocrinol Metab. 2007;  3 748-757
• 2 Bourdeau I, Stratakis C. Cyclic AMP-dependent signaling aberrations in macronodular adrenal disease.  Ann N Y Acad Sci. 2002;  968 240-255
• 3 Kirschner LS, Carney JA, Pack SD, Taymans SE, Giatzakis C, Cho YS, Cho-Chung YS, Stratakis CA. Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex.  Nat Genet. 2000;  26 89-92
• 4 Kirschner LS, Sandrini F, Monbo J, Lin JP, Carney JA, Stratakis CA. Genetic heterogeneity and spectrum of mutations of the PRKAR1A gene in patients with the Carney complex.  Hum Mol Genet. 2000;  9 3037-3046
• 5 Boikos SA, Stratakis CA. Carney complex: the first 20 years.  Curr Opin Oncol. 2007;  19 24-29
• 6 Groussin L, Jullian E, Perlemoine K, Louvel A, Leheup B, Luton JP, Bertagna X, Bertherat J. Mutations of the PRKAR1A gene in Cushing's syndrome due to sporadic primary pigmented nodular adrenocortical disease.  J Clin Endocrinol Metab. 2002;  87 4324-4329
• 7 Gunther DF, Bourdeau I, Matyakhina L, Cassarino D, Kleiner DE, Griffin K, Courkoutsakis N, Abu-Asab M, Tsokos M, Keil M, Carney JA, Stratakis CA. Cyclical Cushing syndrome presenting in infancy: an early form of primary pigmented nodular adrenocortical disease, or a new entity? J Clin Endocrinol Metab 2004; 89: 3173-3182.
• 8 Horvath A, Boikos S, Giatzakis C, Robinson-White A, Groussin L, Griffin KJ, Stein E, Levine E, Delimpasi G, Hsiao HP, Keil M, Heyerdahl S, Matyakhina L, Libe R, Fratticci A, Kirschner LS, Cramer K, Gaillard RC, Bertagna X, Carney JA, Bertherat J, Bossis I, Stratakis CA. A genome-wide scan identifies mutations in the gene encoding phosphodiesterase 11A4 (PDE11A) in individuals with adrenocortical hyperplasia.  Nature Genetics. 2006;  38 794-800
• 9 Horvath A, Giatzakis C, Robinson-White A, Boikos S, Levine E, Griffin K, Stein E, Kamvissi V, Soni P, Bossis I, Herder W de, Carney JA, Bertherat J, Gregersen PK, Remmers EF, Stratakis CA. Adrenal hyperplasia and adenomas are associated with inhibition of phosphodiesterase 11A in carriers of PDE11A sequence variants that are frequent in the population.  Cancer Res. 2006;  66 11571-11575
• 10 Loughney K, Taylor J, Florio VA. 3′,5′-Cyclic nucleotide phosphodiesterase 11A: localization in human tissues.  Int J Impot Res. 2005;  17 320-325
• 11 D’Andrea MR, Qiu Y, Haynes-Johnson D, Bhattacharjee S, Kraft P, Lundeen S. Expression of PDE11A in normal and malignant human tissues.  J Histochem Cytochem. 2005;  53 895-903
• 12 Michibata H, Yanaka N, Kanoh Y, Okumura K, Omori K. Human Ca²⁺/calmodulin-dependent phosphodiesterase PDE1A: novel splice variants, their specific expression, genomic organization, and chromosomal localization.  Biochim Biophys Acta. 2001;  1517 278-287
• 13 Yuasa K, Kanoh Y, Okumura K, Omori K. Genomic organization of the human phosphodiesterase PDE11A gene. Evolutionary relatedness with other PDEs containing GAF domains.  Eur J Biochem. 2001;  268 168-178
• 14 Hetman JM, Robas N, Baxendale R, Fidock M, Phillips SC, Soderling SH, Beavo JA. Cloning and characterization of two splice variants of human phosphodiesterase 11A.  Proc Natl Acad Sci USA. 2000;  97 12891-12895
• 15 Fawcett L, Baxendale R, Stacey P, MacGrouther C, Harrow I, Soderling S, Hetman J, Beavo JA, Phillips SC. Molecular cloning and characterization of a distinct human phosphodiesterase gene family: PDE11A.  Proc Natl Acad Sci USA. 2000;  97 3702-3707
• 16 Yuasa K, Kotera J, Fujishige K, Michibata H, Sasaki T, Omori K. Isolation and characterization of two novel phosphodiesterase PDE11A variants showing unique structure and tissue-specific expression.  J Biol Chem. 2000;  275 31469-31479
• 17 Yuasa K, Ohgaru T, Asahina M, Omori K. Identification of rat cyclic nucleotide phosphodiesterase 11A (PDE11A): comparison of rat and human PDE11A splicing variants.  Eur J Biochem. 2001;  268 4440-4448
• 18 Yuasa K, Kanoh Y, Okumura K, Omori K. Genomic organization of the human phosphodiesterase PDE11A gene. Evolutionary relatedness with other PDEs containing GAF domains.  Eur J Biochem. 2001;  268 168-178
• 19 Toydemir RM, Chen H, Proud VK, Martin R, Bokhoven H van, Hamel BC, Tuerlings JH, Stratakis CA, Jorde LB, Bamshad MJ. Trismus-pseudocamptodactyly syndrome is caused by recurrent mutation of MYH8.  Am J Med Genet. 2006;  140 2387-2393
• 20 Boshart M, Weih F, Nichols M, Schütz G. The tissue-specific extinguisher locus TSE1 encodes a regulatory subunit of cAMP-dependent protein kinase.  Cell. 1991;  66 849-859
• 21 Kim C, Cheng CY, Saldanha SA, Taylor SS. PKA-I holoenzyme structure reveals a mechanism for cAMP-dependent activation.  Cell. 2007;  130 1032-1043
• 22 Stratakis CA. Adrenocortical tumors, primary pigmented adrenocortical disease (PPNAD)/Carney complex, and other bilateral hyperplasias: the NIH studies.  Horm Metab Res. 2007;  39 467-473
• 23 Stratakis CA, Kirschner LS. Clinical and genetic analysis of primary bilateral adrenal diseases (micro- and macronodular disease) leading to Cushing syndrome.  Horm Metab Res. 1998;  30 456-463
• 24 Horvath A, Mericq V, Stratakis CA. Mutation in PDE8B, a cAMP-specific phosphodiesterase in adrenal hyperplasia.  N Engl J Med. 2008;  358 750-752
• 25 . , Almeida MQ, Latronico AC. The molecular pathogenesis of childhood adrenocortical tumors. Horm Metab Res 2007; 39: 461-466

1 Current Affiliation: University of Maryland, School of Veterinary Medicine, College Park, MD, USA

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