How does cAMP/protein kinase A signaling lead to tumors in the adrenal cortex and other tissues?

Molecular and Cellular Endocrinology

Volumn 336, Issue 1-2, 2011, Pages 162-168

  Almeida, Madson Q ^a   Stratakis, Constantine A ^a  

^a EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT   (United States)

Author keywords

ACTH independent macronodular adrenal hyperplasia; Adrenal cortex; Adrenal tumor; Phosphodiesterase; Primary pigmented nodular adrenocortical disease; Protein kinase A; Wnt signaling

Indexed keywords

BETA CATENIN; CYCLIC AMP; CYCLIC AMP DEPENDENT PROTEIN KINASE; CYCLIC AMP DEPENDENT PROTEIN KINASE REGULATORY SUBUNIT IALPHA; GLYCOGEN SYNTHASE KINASE 3BETA; HYDROCORTISONE; PHOSPHODIESTERASE; PHOSPHODIESTERASE 11A; PHOSPHODIESTERASE 8B; UNCLASSIFIED DRUG; WNT PROTEIN;

ADRENAL CORTEX INSUFFICIENCY; ADRENAL CORTEX TUMOR; CARNEY COMPLEX; CUSHING SYNDROME; DISEASE MODEL; ENZYME DEFICIENCY; ENZYME REGULATION; HUMAN; NONHUMAN; PATHOGENESIS; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION; SOMATIC MUTATION;

ADRENAL CORTEX; ADRENAL CORTEX NEOPLASMS; ANIMALS; CYCLIC AMP; CYCLIC AMP-DEPENDENT PROTEIN KINASES; DISEASE MODELS, ANIMAL; HUMANS; SIGNAL TRANSDUCTION;

EID: 79952070409     PISSN: 03037207     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.mce.2010.11.018     Document Type: Review

References (72)

1. Almeida M.Q., Muchow M., Boikos S., Bauer A.J., Griffin K.J., Tsang K.M., Cheadle C., Watkins T., Wen F., Starost M.F., Bossis I., Nesterova M., Stratakis C.A. 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. 2010, 19:1387-1398.
2. Almeida, M.Q., Tsang, K.M., Cheadle, C., Watkins, T., Grivel, J.C., Nesterova, M., Goldbach-Mansky, R., Stratakis, C.A. Protein kinase A regulates caspase-1 via Ets-1 in bone stromal cell-derived lesions: a link between cyclic AMP and pro-inflammatory pathways in osteoblast progenitors. Hum. Mol. Genet. in press.
3. Bertherat J., Groussin L., Sandrini F., Matyakhina L., Bei T., Stergiopoulos S., Papageorgiou T., Bourdeau I., Kirschner L.S., Vincent-Dejean C., Perlemoine K., Gicquel C., Bertagna X., Stratakis C.A. Molecular and functional analysis of PRKAR1A and its locus (17q22-24) in sporadic adrenocortical tumors: 17q losses, somatic mutations, and protein kinase A expression and activity. Cancer Res. 2003, 63:5308-5319.
4. Bertherat J., Horvath A., Groussin L., Grabar S., Boikos S., Cazabat L., Libe R., Rene-Corail F., Stergiopoulos S., Bourdeau I., Bei T., Clauser E., Calender A., Kirschner L.S., Bertagna X., Carney J.A., Stratakis C.A. Mutations in regulatory subunit type 1A of cyclic adenosine 5'-monophosphate-dependent protein kinase (PRKAR1A): phenotype analysis in 353 patients and 80 different genotypes. J. Clin. Endocrinol. Metab. 2009, 94:2085-2091.
5. Bimpaki E.I., Iliopoulos D., Moraitis A., Stratakis C.A. MicroRNA signature in massive macronodular adrenocortical disease and implications for adrenocortical tumorigenesis. Clin. Endocrinol. (Oxf) 2009.
6. Bimpaki E.I., Nesterova M., Stratakis C.A. 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. 2009, 161:153-161.
7. Bossis I., Stratakis C.A. Minireview: PRKAR1A: normal and abnormal functions. Endocrinology 2004, 145:5452-5458.
8. Bossis I., Voutetakis A., Bei T., Sandrini F., Griffin K.J., Stratakis C.A. Protein kinase A and its role in human neoplasia: the Carney complex paradigm. Endocr. Relat. Cancer 2004, 11:265-280.
9. Bourdeau I., Antonini S.R., Lacroix A., Kirschner L.S., Matyakhina L., Lorang D., Libutti S.K., Stratakis C.A. Gene array analysis of macronodular adrenal hyperplasia confirms clinical heterogeneity and identifies several candidate genes as molecular mediators. Oncogene 2004, 23:1575-1585.
10. Bourdeau I., Matyakhina L., Stergiopoulos S.G., Sandrini F., Boikos S., Stratakis C.A. 17q22-24 chromosomal losses and alterations of protein kinase a subunit expression and activity in adrenocorticotropin-independent macronodular adrenal hyperplasia. J. Clin. Endocrinol. Metab. 2006, 91:3626-3632.
11. Brembeck F.H., Rosario M., Birchmeier W. Balancing cell adhesion and Wnt signaling, the key role of beta-catenin. Curr. Opin. Genet. Dev. 2006, 16:51-59.
12. Carney J.A., Boccon-Gibod L., Jarka D.E., Tanaka Y., Swee R.G., Unni K.K., Stratakis C.A. Osteochondromyxoma of bone: a congenital tumor associated with lentigines and other unusual disorders. Am. J. Surg. Pathol. 2001, 25:164-176.
13. Carney J.A., Gordon H., Carpenter P.C., Shenoy B.V., Go V.L. The complex of myxomas, spotty pigmentation, and endocrine overactivity. Medicine (Baltimore) 1985, 64:270-283.
14. Chen A.E., Ginty D.D., Fan C.M. Protein kinase A signalling via CREB controls myogenesis induced by Wnt proteins. Nature 2005, 433:317-322.
15. Cichowski K., Shih T.S., Schmitt E., Santiago S., Reilly K., McLaughlin M.E., Bronson R.T., Jacks T. Mouse models of tumor development in neurofibromatosis type 1. Science 1999, 286:2172-2176.
16. Cottrell S., Bicknell D., Kaklamanis L., Bodmer W.F. Molecular analysis of APC mutations in familial adenomatous polyposis and sporadic colon carcinomas. Lancet 1992, 340:626-630.
17. Gamm D.M., Baude E.J., Uhler M.D. The major catalytic subunit isoforms of cAMP-dependent protein kinase have distinct biochemical properties in vitro and in vivo. J. Biol. Chem. 1996, 271:15736-15742.
18. Gaujoux S., Tissier F., Groussin L., Libe R., Ragazzon B., Launay P., Audebourg A., Dousset B., Bertagna X., Bertherat J. Wnt/beta-catenin and 3',5'-cyclic adenosine 5'-monophosphate/protein kinase A signaling pathways alterations and somatic beta-catenin gene mutations in the progression of adrenocortical tumors. J. Clin. Endocrinol. Metab. 2008, 93:4135-4140.
19. Greene E.L., Horvath A.D., Nesterova M., Giatzakis C., Bossis I., Stratakis C.A. In vitro functional studies of naturally occurring pathogenic PRKAR1A mutations that are not subject to nonsense mRNA decay. Hum. Mutat. 2008, 29:633-639.
20. Griffin K.J., Kirschner L.S., Matyakhina L., Stergiopoulos S., Robinson-White A., Lenherr S., Weinberg F.D., Claflin E., Meoli E., Cho-Chung Y.S., Stratakis C.A. Down-regulation of regulatory subunit type 1A of protein kinase A leads to endocrine and other tumors. Cancer Res. 2004, 64:8811-8815.
21. Griffin K.J., Kirschner L.S., Matyakhina L., Stergiopoulos S.G., Robinson-White A., Lenherr S.M., Weinberg F.D., Claflin E.S., Batista D., Bourdeau I., Voutetakis A., Sandrini F., Meoli E.M., Bauer A.J., Cho-Chung Y.S., Bornstein S.R., Carney J.A., Stratakis C.A. A transgenic mouse bearing an antisense construct of regulatory subunit type 1A of protein kinase A develops endocrine and other tumours: comparison with Carney complex and other PRKAR1A induced lesions. J. Med. Genet. 2004, 41:923-931.
22. Groussin L., Kirschner L.S., Vincent-Dejean C., Perlemoine K., Jullian E., Delemer B., Zacharieva S., Pignatelli D., Carney J.A., Luton J.P., Bertagna X., Stratakis C.A., Bertherat J. 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. 2002, 71:1433-1442.
23. Horvath A., Bertherat J., Groussin L., Guillaud-Bataille M., Tsang K., Cazabat L., Libe R., Remmers E., Rene-Corail F., Faucz F.R., Clauser E., Calender A., Bertagna X., Carney J.A., Stratakis C.A. Mutations and polymorphisms in the gene encoding regulatory subunit type 1-alpha of protein kinase A (PRKAR1A): an update. Hum. Mutat. 2010, 31:369-379.
24. Horvath A., Mericq V., Stratakis C.A. Mutation in PDE8B, a cyclic AMP-specific phosphodiesterase in adrenal hyperplasia. N. Engl. J. Med. 2008, 358:750-752.
25. Horvath A., Boikos S., Giatzakis C., Robinson-White A., Groussin L., Griffin K.J., Stein E., Levine E., Delimpasi G., Hsiao H.P., Keil M., Heyerdahl S., Matyakhina L., Libe R., Fratticci A., Kirschner L.S., Cramer K., Gaillard R.C., Bertagna X., Carney J.A., Bertherat J., Bossis I., Stratakis C.A. A genome-wide scan identifies mutations in the gene encoding phosphodiesterase 11A4 (PDE11A) in individuals with adrenocortical hyperplasia. Nat. Genet. 2006, 38:794-800.
26. Horvath A., Giatzakis C., Robinson-White A., Boikos S., Levine E., Griffin K., Stein E., Kamvissi V., Soni P., Bossis I., de Herder W., Carney J.A., Bertherat J., Gregersen P.K., Remmers E.F., Stratakis C.A. 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.
27. Horvath A., Mathyakina L., Vong Q., Baxendale V., Pang A.L., Chan W.Y., Stratakis C.A. Serial analysis of gene expression in adrenocortical hyperplasia caused by a germline PRKAR1A mutation. J. Clin. Endocrinol. Metab. 2006, 91:584-596.
28. Hsiao H.P., Kirschner L.S., Bourdeau I., Keil M.F., Boikos S.A., Verma S., Robinson-White A.J., Nesterova M., Lacroix A., Stratakis C.A. Clinical and genetic heterogeneity, overlap with other tumor syndromes, and atypical glucocorticoid hormone secretion in adrenocorticotropin-independent macronodular adrenal hyperplasia compared with other adrenocortical tumors. J. Clin. Endocrinol. Metab. 2009, 94:2930-2937.
29. Iliopoulos D., Bimpaki E.I., Nesterova M., Stratakis C.A. MicroRNA signature of primary pigmented nodular adrenocortical disease: clinical correlations and regulation of Wnt signaling. Cancer Res. 2009, 69:3278-3282.
30. Jacks T., Fazeli A., Schmitt E.M., Bronson R.T., Goodell M.A., Weinberg R.A. Effects of an Rb mutation in the mouse. Nature 1992, 359:295-300.
31. Johnson D.G., Schwarz J.K., Cress W.D., Nevins J.R. Expression of transcription factor E2F1 induces quiescent cells to enter S phase. Nature 1993, 365:349-352.
32. Kim C., Cheng C.Y., Saldanha S.A., Taylor S.S. PKA-I holoenzyme structure reveals a mechanism for cAMP-dependent activation. Cell 2007, 130:1032-1043.
33. Kirschner L.S., Carney J.A., Pack S.D., Taymans S.E., Giatzakis C., Cho Y.S., Cho-Chung Y.S., Stratakis C.A. 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.
34. Kirschner L.S., Sandrini F., Monbo J., Lin J.P., Carney J.A., Stratakis C.A. Genetic heterogeneity and spectrum of mutations of the PRKAR1A gene in patients with the Carney complex. Hum. Mol. Genet. 2000, 9:3037-3046.
35. Kirschner L.S., Kusewitt D.F., Matyakhina L., Towns W.H., Carney J.A., Westphal H., Stratakis C.A. A mouse model for the Carney complex tumor syndrome develops neoplasia in cyclic AMP-responsive tissues. Cancer Res. 2005, 65:4506-4514.
36. Klaus A., Birchmeier W. Wnt signalling and its impact on development and cancer. Nat. Rev. Cancer 2008, 8:387-398.
37. Lacroix A. ACTH-independent macronodular adrenal hyperplasia. Best Pract. Res. Clin. Endocrinol. Metab. 2009, 23:245-259.
38. Lacroix A., Baldacchino V., Bourdeau I., Hamet P., Tremblay J. Cushing's syndrome variants secondary to aberrant hormone receptors. Trends Endocrinol. Metab. 2004, 15:375-382.
39. Lacroix A., Ndiaye N., Tremblay J., Hamet P. Ectopic and abnormal hormone receptors in adrenal Cushing's syndrome. Endocr. Rev. 2001, 22:75-110.
40. Lee P.A., Van Dop C., Migeon C.J. McCune-Albright syndrome. Long-term follow-up. JAMA 1986, 256:2980-2984.
41. Mavrakis M., Lippincott-Schwartz J., Stratakis C.A., Bossis I. Depletion of type IA regulatory subunit (RIalpha) of protein kinase A (PKA) in mammalian cells and tissues activates mTOR and causes autophagic deficiency. Hum. Mol. Genet. 2006, 15:2962-2971.
42. McKnight G.S., Clegg C.H., Uhler M.D., Chrivia J.C., Cadd G.G., Correll L.A., Otten A.D. Analysis of the cAMP-dependent protein kinase system using molecular genetic approaches. Recent Prog. Horm. Res. 1988, 44:307-335.
43. Meoli E., Bossis I., Cazabat L., Mavrakis M., Horvath A., Stergiopoulos S., Shiferaw M.L., Fumey G., Perlemoine K., Muchow M., Robinson-White A., Weinberg F., Nesterova M., Patronas Y., Groussin L., Bertherat J., Stratakis C.A. Protein kinase A effects of an expressed PRKAR1A mutation associated with aggressive tumors. Cancer Res. 2008, 68:3133-3141.
44. Molyneux S.D., Di Grappa M.A., Beristain A.G., McKee T.D., Wai D.H., Paderova J., Kashyap M., Hu P., Maiuri T., Narala S.R., Stambolic V., Squire J., Penninger J., Sanchez O., Triche T.J., Wood G.A., Kirschner L.S., Khokha R. Prkar1a is an osteosarcoma tumor suppressor that defines a molecular subclass in mice. J. Clin. Invest. 2010, 120:3310-3325.
45. Nadella K.S., Kirschner L.S. Disruption of protein kinase a regulation causes immortalization and dysregulation of D-type cyclins. Cancer Res. 2005, 65:10307-10315.
46. Nesterova M., Bossis I., Wen F., Horvath A., Matyakhina L., Stratakis C.A. 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. 2008, 93:565-571.
47. Pavel E., Nadella K., Towns W.H., Kirschner L.S. Mutation of Prkar1a causes osteoblast neoplasia driven by dysregulation of protein kinase A. Mol. Endocrinol. 2008, 22:430-440.
48. Pearce L.R., Komander D., Alessi D.R. The nuts and bolts of AGC protein kinases. Nat. Rev. Mol. Cell Biol. 2010, 11:9-22.
49. Polakis P. Wnt signaling and cancer. Genes Dev. 2000, 14:1837-1851.
50. Powell S.M., Zilz N., Beazer-Barclay Y., Bryan T.M., Hamilton S.R., Thibodeau S.N., Vogelstein B., Kinzler K.W. APC mutations occur early during colorectal tumorigenesis. Nature 1992, 359:235-237.
51. Qin X.Q., Livingston D.M., Kaelin W.G., Adams P.D. Deregulated transcription factor E2F-1 expression leads to S-phase entry and p53-mediated apoptosis. Proc. Natl. Acad. Sci. U.S.A. 1994, 91:10918-10922.
52. Ragazzon B., Cazabat L., Rizk-Rabin M., Assie G., Groussin L., Fierrard H., Perlemoine K., Martinez A., Bertherat J. Inactivation of the Carney complex gene 1 (protein kinase A regulatory subunit 1A) inhibits SMAD3 expression and TGF beta-stimulated apoptosis in adrenocortical cells. Cancer Res. 2009, 69:7278-7284.
53. Robinson-White A., Hundley T.R., Shiferaw M., Bertherat J., Sandrini F., Stratakis C.A. Protein kinase-A activity in PRKAR1A-mutant cells, and regulation of mitogen-activated protein kinases ERK1/2. Hum. Mol. Genet. 2003, 12:1475-1484.
54. Robinson-White A., Meoli E., Stergiopoulos S., Horvath A., Boikos S., Bossis I., Stratakis C.A. PRKAR1A mutations and protein kinase A interactions with other signaling pathways in the adrenal cortex. J. Clin. Endocrinol. Metab. 2006, 91:2380-2388.
55. Robinson-White A.J., Leitner W.W., Aleem E., Kaldis P., Bossis I., Stratakis C.A. PRKAR1A inactivation leads to increased proliferation and decreased apoptosis in human B lymphocytes. Cancer Res. 2006, 66:10603-10612.
56. Roy L., McDonald C.A., Jiang C., Maroni D., Zeleznik A.J., Wyatt T.A., Hou X., Davis J.S. Convergence of 3',5'-cyclic adenosine 5'-monophosphate/protein kinase A and glycogen synthase kinase-3beta/beta-catenin signaling in corpus luteum progesterone synthesis. Endocrinology 2009, 150:5036-5045.
57. Sahut-Barnola I., de Joussineau C., Val P., Lambert-Langlais S., Damon C., Lefrancois-Martinez A.M., Pointud J.C., Marceau G., Sapin V., Tissier F., Ragazzon B., Bertherat J., Kirschner L.S., Stratakis C.A., Martinez A. Cushing's syndrome and fetal features resurgence in adrenal cortex-specific Prkar1a knockout mice. PLoS Genet. 2010, 6:e1000980.
58. Sewing A., Muller R. Protein kinase A phosphorylates cyclin D1 at three distinct sites within the cyclin box and at the C-terminus. Oncogene 1994, 9:2733-2736.
59. Skalhegg B.S., Tasken K. Specificity in the cAMP/PKA signaling pathway. Differential expression, regulation, and subcellular localization of subunits of PKA. Front. Biosci. 2000, 5:D678-D693.
60. Stratakis C.A. New genes and/or molecular pathways associated with adrenal hyperplasias and related adrenocortical tumors. Mol. Cell. Endocrinol. 2009, 300:152-157.
61. Stratakis C.A., Kirschner L.S. Clinical and genetic analysis of primary bilateral adrenal diseases (micro- and macronodular disease) leading to Cushing syndrome. Horm. Metab. Res. 1998, 30:456-463.
62. Stratakis C.A., Kirschner L.S., Carney J.A. Clinical and molecular features of the Carney complex: diagnostic criteria and recommendations for patient evaluation. J. Clin. Endocrinol. Metab. 2001, 86:4041-4046.
63. Tadjine M., Lampron A., Ouadi L., Horvath A., Stratakis C.A., Bourdeau I. Detection of somatic beta-catenin mutations in primary pigmented nodular adrenocortical disease (PPNAD). Clin. Endocrinol. (Oxf) 2008, 69:367-373.
64. Takeda H., Miyoshi H., Kojima Y., Oshima M., Taketo M.M. Accelerated onsets of gastric hamartomas and hepatic adenomas/carcinomas in Lkb1+/-p53-/- compound mutant mice. Oncogene 2006, 25:1816-1820.
65. Tissier F., Cavard C., Groussin L., Perlemoine K., Fumey G., Hagnere A.M., Rene-Corail F., Jullian E., Gicquel C., Bertagna X., Vacher-Lavenu M.C., Perret C., Bertherat J. Mutations of beta-catenin in adrenocortical tumors: activation of the Wnt signaling pathway is a frequent event in both benign and malignant adrenocortical tumors. Cancer Res. 2005, 65:7622-7627.
66. Tsang K.M., Starost M.F., Nesterova M., Boikos S.A., Watkins T., Almeida M.Q., Harran M., Li A., Collins M.T., Cheadle C., Mertz E.L., Leikin S., Kirschner L.S., Robey P., Stratakis C.A. Alternate protein kinase A activity identifies a unique population of stromal cells in adult bone. Proc. Natl. Acad. Sci. U.S.A. 2010, 107:8683-8688.
67. Uhler M.D., McKnight G.S. Expression of cDNAs for two isoforms of the catalytic subunit of cAMP-dependent protein kinase. J. Biol. Chem. 1987, 262:15202-15207.
68. Vogel K.S., Klesse L.J., Velasco-Miguel S., Meyers K., Rushing E.J., Parada L.F. Mouse tumor model for neurofibromatosis type 1. Science 1999, 286:2176-2179.
69. Weinstein L.S., Shenker A., Gejman P.V., Merino M.J., Friedman E., Spiegel A.M. Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. N. Engl. J. Med. 1991, 325:1688-1695.
70. Wilson C.H., McIntyre R.E., Arends M.J., Adams D.J. The activating mutation R201C in GNAS promotes intestinal tumourigenesis in Apc(Min/+) mice through activation of Wnt and ERK1/2 MAPK pathways. Oncogene 2010, 29:4567-4575.
71. Wong W., Scott J.D. AKAP signalling complexes: focal points in space and time. Nat. Rev. Mol. Cell Biol. 2004, 5:959-970.
72. Zhang L., Smyrk T.C., Young W.F., Stratakis C.A., Carney J.A. Gastric stromal tumors in Carney triad are different clinically. pathologically, and behaviorally from sporadic gastric gastrointestinal stromal tumors: findings in 104 cases. Am. J. Surg. Pathol. 2009.