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Phosphodiesterase 8B and cyclic AMP signaling in the adrenal cortex

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Abstract

Bilateral adrenocortical hyperplasia (BAH) in humans and mice has been recently linked to phosphodiesterase (PDE) 8B (PDE8B) and 11 (PDE11A) defects. These findings have followed the discovery that defects of primary genes of the cyclic monophosphatase (cAMP) signaling pathway, such as guanine nucleotide binding alpha subunit and PRKAR1A, are involved in the pathogenesis of BAH in humans; complete absence of Prkar1a in the adrenal cortex of mice also led to pathology that mimicked the human disease. Here, we review the most recent findings in human and mouse studies on PDE8B, a cAMP-specific PDE that appears to be highly expressed in the adrenal cortex and whose deficiency may underlie predisposition to BAH and possibly other human diseases.

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References

  1. C.A. Stratakis, Cyclic AMP, protein kinase A, and phosphodiesterases: proceedings of an international workshop. Horm. Metab. Res. 44, 713–715 (2012)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. A. Horvath, C. Giatzakis, K. Tsang, E. Greene, P. Osorio, S. Boikos, R. Libe, Y. Patronas, A. Robinson-White, E. Remmers, J. Bertherat, M. Nesterova, C.A. Stratakis, A cAMP-specific phosphodiesterase (PDE8B) that is mutated in adrenal hyperplasia is expressed widely in human and mouse tissues: a novel PDE8B isoform in human adrenal cortex. Eur. J. Hum. Genet. 16, 1245–1253 (2008)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. A. Horvath, V. Mericq, C.A. Stratakis, Mutation in PDE8B, a cyclic AMP-specific phosphodiesterase in adrenal hyperplasia. N. Engl. J. Med. 358, 750–752 (2008)

    Article  CAS  PubMed  Google Scholar 

  4. A. Rothenbuhler, A. Horvath, R. Libe, F.R. Faucz, A. Fratticci, M.L. Raffin Sanson, D. Vezzosi, M. Azevedo, I. Levy, M.Q. Almeida, M. Lodish, M. Nesterova, J. Bertherat, C.A. Stratakis, Identification of novel genetic variants in phosphodiesterase 8B (PDE8B), a cAMP-specific phosphodiesterase highly expressed in the adrenal cortex, in a cohort of patients with adrenal tumours. Clin. Endocrinol. (Oxf.) 77, 195–199 (2012)

    Article  CAS  Google Scholar 

  5. E.I. Bimpaki, M. Nesterova, C.A. Stratakis, Abnormalities of cAMP signaling are present in adrenocortical lesions associated with ACTH-independent Cushing syndrome despite the absence of mutations in known genes. Eur. J. Endocrinol. 161, 153–161 (2009)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. L. Cazabat, B. Ragazzon, L. Groussin, J. Bertherat, PRKAR1A mutations in primary pigmented nodular adrenocortical disease. Pituitary 9, 211–219 (2006)

    Article  CAS  PubMed  Google Scholar 

  7. L. Groussin, L.S. Kirschner, C. Vincent-Dejean, K. Perlemoine, E. Jullian, B. Delemer, S. Zacharieva, D. Pignatelli, J.A. Carney, J.P. Luton, X. Bertagna, C.A. Stratakis, J. Bertherat, Molecular analysis of the cyclic AMP-dependent protein kinase A (PKA) regulatory subunit 1A (PRKAR1A) gene in patients with Carney complex and primary pigmented nodular adrenocortical disease (PPNAD) reveals novel mutations and clues for pathophysiology: augmented PKA signaling is associated with adrenal tumorigenesis in PPNAD. Am. J. Hum. Genet. 71, 1433–1442 (2002)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. L.S. Kirschner, F. Sandrini, J. Monbo, J.P. Lin, J.A. Carney, C.A. Stratakis, Genetic heterogeneity and spectrum of mutations of the PRKAR1A gene in patients with the carney complex. Hum. Mol. Genet. 9, 3037–3046 (2000)

    Article  CAS  PubMed  Google Scholar 

  9. E. Meoli, I. Bossis, L. Cazabat, M. Mavrakis, A. Horvath, S. Stergiopoulos, M.L. Shiferaw, G. Fumey, K. Perlemoine, M. Muchow, A. Robinson-White, F. Weinberg, M. Nesterova, Y. Patronas, L. Groussin, J. Bertherat, C.A. Stratakis, Protein kinase A effects of an expressed PRKAR1A mutation associated with aggressive tumors. Cancer Res. 68, 3133–3141 (2008)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. F. Beuschlein, M. Fassnacht, G. Assie, D. Calebiro, C.A. Stratakis, A. Osswald, C.L. Ronchi, T. Wieland, S. Sbiera, F.R. Faucz, K. Schaak, A. Schmittfull, T. Schwarzmayr, O. Barreau, D. Vezzosi, M. Rizk-Rabin, U. Zabel, E. Szarek, P. Salpea, A. Forlino, A. Vetro, O. Zuffardi, C. Kisker, S. Diener, T. Meitinger, M.J. Lohse, M. Reincke, J. Bertherat, T.M. Strom, B. Allolio, Constitutive activation of PKA catalytic subunit in adrenal Cushing’s syndrome. N. Engl. J. Med. 370, 1019–1028 (2014)

    Article  CAS  PubMed  Google Scholar 

  11. S.R. Antonini, M.C. Fragoso, Lacroix A [Clinical and molecular aspects of the ACTH-independent bilateral macronodular adrenal hyperplasia]. Arq. Bras. Endocrinol. Metabol. 48, 620–636 (2004)

    Article  PubMed  Google Scholar 

  12. L.S. Weinstein, A. Shenker, P.V. Gejman, M.J. Merino, E. Friedman, A.M. Spiegel, Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. N. Engl. J. Med. 325, 1688–1695 (1991)

    Article  CAS  PubMed  Google Scholar 

  13. B.A. Boston, S. Mandel, S. LaFranchi, M. Bliziotes, Activating mutation in the stimulatory guanine nucleotide-binding protein in an infant with Cushing’s syndrome and nodular adrenal hyperplasia. J. Clin. Endocrinol. Metab. 79, 890–893 (1994)

    CAS  PubMed  Google Scholar 

  14. M.Q. Almeida, M.F. Azevedo, P. Xekouki, E.I. Bimpaki, A. Horvath, M.T. Collins, L.P. Karaviti, G.S. Jeha, N. Bhattacharyya, C. Cheadle, T. Watkins, I. Bourdeau, M. Nesterova, C.A. Stratakis, Activation of cyclic AMP signaling leads to different pathway alterations in lesions of the adrenal cortex caused by germline PRKAR1A defects versus those due to somatic GNAS mutations. J. Clin. Endocrinol. Metab. 97, E687–E693 (2012)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. S.H. Soderling, S.J. Bayuga, J.A. Beavo, Identification and characterization of a novel family of cyclic nucleotide phosphodiesterases. J. Biol. Chem. 273, 15553–15558 (1998)

    Article  CAS  PubMed  Google Scholar 

  16. L.C. Tsai, J.A. Beavo, The roles of cyclic nucleotide phosphodiesterases (PDEs) in steroidogenesis. Curr. Opin. Pharmacol. 11, 670–675 (2011)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. C. Chen, J. Wickenheisser, K.G. Ewens, W. Ankener, R.S. Legro, A. Dunaif, J.M. McAllister, R.S. Spielman, J.F. Strauss 3rd, PDE8A genetic variation, polycystic ovary syndrome and androgen levels in women. Mol. Hum. Reprod. 15, 459–469 (2009)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. L.C. Tsai, M. Shimizu-Albergine, J.A. Beavo, The high-affinity cAMP-specific phosphodiesterase 8B controls steroidogenesis in the mouse adrenal gland. Mol. Pharmacol. 79, 639–648 (2011)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. A. Horvath, S. Boikos, C. Giatzakis, A. Robinson-White, L. Groussin, K.J. Griffin, E. Stein, E. Levine, G. Delimpasi, H.P. Hsiao, M. Keil, S. Heyerdahl, L. Matyakhina, R. Libe, A. Fratticci, L.S. Kirschner, K. Cramer, R.C. Gaillard, X. Bertagna, J.A. Carney, J. Bertherat, I. Bossis, C.A. Stratakis, A genome-wide scan identifies mutations in the gene encoding phosphodiesterase 11A4 (PDE11A) in individuals with adrenocortical hyperplasia. Nat. Genet. 38, 794–800 (2006)

    Article  CAS  PubMed  Google Scholar 

  20. L. Groussin, E. Jullian, K. Perlemoine, A. Louvel, B. Leheup, J.P. Luton, X. Bertagna, J. Bertherat, Mutations of the PRKAR1A gene in Cushing’s syndrome due to sporadic primary pigmented nodular adrenocortical disease. J. Clin. Endocrinol. Metab. 87, 4324–4329 (2002)

    Article  CAS  PubMed  Google Scholar 

  21. B. Yu, B. Ragazzon, M. Rizk-Rabin, J. Bertherat. Protein kinase a alterations in endocrine tumors. Horm. Metab. Res. 44, 741–748

  22. P.S. Amieux, D.G. Howe, H. Knickerbocker, D.C. Lee, T. Su, G.S. Laszlo, R.L. Idzerda, G.S. McKnight, Increased basal cAMP-dependent protein kinase activity inhibits the formation of mesoderm-derived structures in the developing mouse embryo. J. Biol. Chem. 277, 27294–27304 (2002)

    Article  CAS  PubMed  Google Scholar 

  23. L.S. Kirschner, D.F. Kusewitt, L. Matyakhina, W.H. Towns 2nd, J.A. Carney, H. Westphal, C.A. Stratakis, A mouse model for the Carney complex tumor syndrome develops neoplasia in cyclic AMP-responsive tissues. Cancer Res. 65, 4506–4514 (2005)

    Article  CAS  PubMed  Google Scholar 

  24. G.N. Jones, C. Tep, W.H. Towns 2nd, G. Mihai, I.D. Tonks, G.F. Kay, P.M. Schmalbrock, A.O. Stemmer-Rachamimov, S.O. Yoon, L.S. Kirschner, Tissue-specific ablation of Prkar1a causes schwannomas by suppressing neurofibromatosis protein production. Neoplasia 10, 1213–1221 (2008)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Z. Yin, G.N. Jones, W.H. Towns 2nd, X. Zhang, E.D. Abel, P.F. Binkley, D. Jarjoura, L.S. Kirschner, Heart-specific ablation of Prkar1a causes failure of heart development and myxomagenesis. Circulation 117, 1414–1422 (2008)

    Article  CAS  PubMed  Google Scholar 

  26. Z. Yin, L. Williams-Simons, A.F. Parlow, S. Asa, L.S. Kirschner, Pituitary-specific knockout of the Carney complex gene Prkar1a leads to pituitary tumorigenesis. Mol. Endocrinol. 22, 380–387 (2008)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. I. Sahut-Barnola, C. de Joussineau, P. Val, S. Lambert-Langlais, C. Damon, A.M. Lefrancois-Martinez, J.C. Pointud, G. Marceau, V. Sapin, F. Tissier, B. Ragazzon, J. Bertherat, L.S. Kirschner, C.A. Stratakis, A. Martinez. Cushing’s syndrome and fetal features resurgence in adrenal cortex-specific Prkar1a knockout mice. PLoS Genet. 6, e1000980

  28. M.Q. Almeida, M. Muchow, S. Boikos, A.J. Bauer, K.J. Griffin, K.M. Tsang, C. Cheadle, T. Watkins, F. Wen, M.F. Starost, I. Bossis, M. Nesterova, C.A. Stratakis. Mouse Prkar1a haploinsufficiency leads to an increase in tumors in the Trp53 ± or Rb1 ± backgrounds and chemically induced skin papillomas by dysregulation of the cell cycle and Wnt signaling. Hum. Mol. Genet. 19, 1387–1398

  29. M. Nesterova, I. Bossis, F. Wen, A. Horvath, L. Matyakhina, C.A. Stratakis, An immortalized human cell line bearing a PRKAR1A-inactivating mutation: effects of overexpression of the wild-type Allele and other protein kinase A subunits. J. Clin. Endocrinol. Metab. 93, 565–571 (2008)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. B.S. Skalhegg, Y. Huang, T. Su, R.L. Idzerda, G.S. McKnight, K.A. Burton, Mutation of the Calpha subunit of PKA leads to growth retardation and sperm dysfunction. Mol. Endocrinol. 16, 630–639 (2002)

    CAS  PubMed  Google Scholar 

  31. C.A. Stratakis, E pluribus unum? The main protein kinase A catalytic subunit (PRKACA), a likely oncogene, and cortisol-producing tumors. J. Clin. Endocrinol. Metab. 99, 3629–3633 (2014)

    Article  CAS  PubMed  Google Scholar 

  32. J.A. Carney, C. Lyssikatos, M.B. Lodish, C.A. Stratakis, Germline PRKACA amplification leads to Cushing syndrome caused by 3 adrenocortical pathologic phenotypes. Hum. Pathol. 46, 40–49 (2015)

    Article  CAS  PubMed  Google Scholar 

  33. Y.S. Cho-Chung, S. Pepe, T. Clair, A. Budillon, M. Nesterova, cAMP-dependent protein kinase: role in normal and malignant growth. Crit. Rev. Oncol. Hematol. 21, 33–61 (1995)

    Article  CAS  PubMed  Google Scholar 

  34. G. Di Dalmazi, C. Kisker, D. Calebiro, M. Mannelli, L. Canu, G. Arnaldi, M. Quinkler, N. Rayes, A. Tabarin, M. Laure Jullie, F. Mantero, B. Rubin, J. Waldmann, D.K. Bartsch, R. Pasquali, M. Lohse, B. Allolio, M. Fassnacht, F. Beuschlein, M. Reincke. Novel somatic mutations in the catalytic subunit of the protein kinase A as a cause of adrenal Cushing’s syndrome: a European multicentric study. J. Clin. Endocrinol. Metab. jc20142152 (2014)

  35. G. Goh, U.I. Scholl, J.M. Healy, M. Choi, M.L. Prasad, C. Nelson-Williams, J.W. Kunstman, R. Korah, A.C. Suttorp, D. Dietrich, M. Haase, H.S. Willenberg, P. Stalberg, P. Hellman, G. Akerstrom, P. Bjorklund, T. Carling, R.P. Lifton, Recurrent activating mutation in PRKACA in cortisol-producing adrenal tumors. Nat. Genet. 46, 613–617 (2014)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. K.M. Tsang, M.F. Starost, M. Nesterova, S.A. Boikos, T. Watkins, M.Q. Almeida, M. Harran, A. Li, M.T. Collins, C. Cheadle, E.L. Mertz, S. Leikin, L.S. Kirschner, P. Robey, C.A. Stratakis, Alternate protein kinase A activity identifies a unique population of stromal cells in adult bone. Proc. Natl. Acad. Sci. USA 107, 8683–8688 (2010)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgment

This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. No research was conducted involving human articipants and/or animals (we only reviewed the relevant literature) in the present report.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Section on Endocrinology and Genetics, Program on Developmental Endocrinology & Genetics (PDEGEN) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, 10 Center Drive, Building 10, NIH-Clinical Research Center, Room 1-3216, Bethesda, MD, 20892, USA

    Leticia Ferro Leal, Eva Szarek, Fabio Faucz & Constantine A. Stratakis

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  1. Leticia Ferro Leal
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  2. Eva Szarek
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  3. Fabio Faucz
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  4. Constantine A. Stratakis
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Correspondence to Eva Szarek.

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Leal, L.F., Szarek, E., Faucz, F. et al. Phosphodiesterase 8B and cyclic AMP signaling in the adrenal cortex. Endocrine 50, 27–31 (2015). https://doi.org/10.1007/s12020-015-0621-y

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