Download PDF
Horm Metab Res 2012; 44(10): 741-748
DOI: 10.1055/s-0032-1316292
Review
© Georg Thieme Verlag KG Stuttgart · New York

Protein Kinase A Alterations in Endocrine Tumors

B. Yu
1   Institut Cochin, INSERM U1016, Paris, France
2   CNRS UMR8104, Paris, France
3   Sorbonne Paris Cité, Université Paris Descartes, Paris, France
,
B. Ragazzon
1   Institut Cochin, INSERM U1016, Paris, France
2   CNRS UMR8104, Paris, France
3   Sorbonne Paris Cité, Université Paris Descartes, Paris, France
,
M. Rizk-Rabin
1   Institut Cochin, INSERM U1016, Paris, France
2   CNRS UMR8104, Paris, France
3   Sorbonne Paris Cité, Université Paris Descartes, Paris, France
,
J. Bertherat
1   Institut Cochin, INSERM U1016, Paris, France
2   CNRS UMR8104, Paris, France
3   Sorbonne Paris Cité, Université Paris Descartes, Paris, France
4   Assistance Publique Hôpitaux de Paris, Center for Rare Adrenal Diseases, Hôpital Cochin, Paris, France
› Author Affiliations
Further Information

Publication History

received 28 December 2011

accepted 23 May 2012

Publication Date:
29 June 2012 (online)

Also available at
    Permissions and Reprints

Abstract

Various molecular and cellular alterations of the cyclic adenosine monophosphate (cAMP) pathway have been observed in endocrine tumors. Since protein kinase A (PKA) is a central key component of the cAMP pathway, studies of the alterations of PKA subunits in endocrine tumors reveal new aspects of the mechanisms of cAMP pathway alterations in human diseases. So far, most alterations have been observed for the regulatory subunits, mainly PRKAR1A and to a lower extent, PRKAR2B. One of the best examples of such alteration today is the multiple neoplasia syndrome Carney complex (CNC). The most common endocrine gland manifestations of CNC are pituitary GH-secreting adenomas, thyroid tumors, testicular tumors, and ACTH-independent Cushing’s syndrome due to primary pigmented nodular adrenocortical disease (PPNAD). Heterozygous germline inactivating mutations of the PKA regulatory subunit RIα gene (PRKAR1A) are observed in about two-third of CNC patients, and also in patients with isolated PPNAD. PRKAR1A is considered as a tumor suppressor gene. Interestingly, these mutations can also be observed as somatic alterations in sporadic endocrine tumors. More than 120 different PRKAR1A mutations have been found today. Most of them lead to an unstable mutant mRNA, which will be degraded by nonsense mediated mRNA decay. In vitro and in vivo functional studies are in progress to understand the mechanisms of endocrine tumor development due to PKA regulatory subunits inactivation. PRKAR1A mutations stimulate in most models PKA activity, mimicking in some way cAMP pathway constitutive activation. Cross-talks with other signaling pathways summarized in this review have been described and might participate in endocrine tumorigenesis.

Key words

cAMP - PKA - adrenal tumors - pituitary tumors
 

  • References

  • 1 Gloerich M, Bos JL. Epac: defining a new mechanism for cAMP action. Annu Rev Pharmacol Toxicol 2010; 50: 355-375
    CrossrefPubMedGoogle Scholar
  • 2 Corbin JD, Keely SL, Park CR. The distribution and dissociation of cyclic adenosine 3′:5′-monophosphate-dependent protein kinases in adipose, cardiac, and other tissues. J Biol Chem 1975; 250: 218-225
    PubMedGoogle Scholar
  • 3 Pearce LR, Komander D, Alessi DR. The nuts and bolts of AGC protein kinases. Nat Rev Mol Cell Biol 2010; 11: 9-22
    CrossrefPubMedGoogle Scholar
  • 4 Shabb JB. Physiological substrates of cAMP-dependent protein kinase. Chem Rev 2001; 101: 2381-2411
    CrossrefPubMedGoogle Scholar
  • 5 Landis CA, Masters SB, Spada A, Pace AM, Bourne HR, Vallar L. GTPase inhibiting mutations activate the alpha chain of Gs and stimulate adenylyl cyclase in human pituitary tumours. Nature 1989; 340: 692-696
    Google Scholar
  • 6 Weinstein LS, Shenker A, Gejman PV, Merino MJ, Friedman E, Spiegel AM. Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. N Engl J Med 1991; 325: 1688-1695
    Google Scholar
  • 7 Porcellini A, Ciullo I, Pannain S, Fenzi G, Avvedimento E. Somatic mutations in the VI transmembrane segment of the thyrotropin receptor constitutively activate cAMP signalling in thyroid hyperfunctioning adenomas. Oncogene 1995; 11: 1089-1093
    PubMedGoogle Scholar
  • 8 Horvath A, Mericq V, Stratakis CA. Mutation in PDE8B, a cyclic AMP-specific phosphodiesterase in adrenal hyperplasia. N Engl J Med 2008; 358: 750-752
    CrossrefPubMedGoogle Scholar
  • 9 Libe R, Horvath A, Vezzosi D, Fratticci A, Coste J, Perlemoine K, Ragazzon B, Guillaud-Bataille M, Groussin L, Clauser E, Raffin-Sanson ML, Siegel J, Moran J, Drori-Herishanu L, Faucz FR, Lodish M, Nesterova M, Bertagna X, Bertherat J, Stratakis CA. Frequent phosphodiesterase 11A gene (PDE11A) defects in patients with Carney complex (CNC) caused by PRKAR1A mutations: PDE11A may contribute to adrenal and testicular tumors in CNC as a modifier of the phenotype. J Clin Endocrinol Metab 2011; 96: E208-E214
    CrossrefPubMedGoogle Scholar
  • 10 Riou JP, Evain D, Perrin F, Saez JM. Adenosine 3′5′-cyclic monophosphate dependent protein kinase in human adrenocortical tumors. J Clin Endocrinol Metab 1977; 44: 413-419
    CrossrefPubMedGoogle Scholar
  • 11 Carney JA, Gordon H, Carpenter PC, Shenoy BV, Go VL. The complex of myxomas, spotty pigmentation, and endocrine overactivity. Medicine (Baltimore) 1985; 64: 270-283
    CrossrefPubMedGoogle Scholar
  • 12 Stratakis CA. Genetics of adrenocortical tumors: Carney complex. Ann Endocrinol (Paris). 2001. 62. 180-184
    Google Scholar
  • 13 Vezzosi D, Bertherat J, Groussin L. Pathogenesis of benign adrenocortical tumors. Best Pract Res Clin Endocrinol Metab 2010; 24: 893-905
    CrossrefPubMedGoogle Scholar
  • 14 Rothenbuhler A, Stratakis CA. Clinical and molecular genetics of Carney complex. Best Pract Res Clin Endocrinol Metab 2010; 24: 389-399
    CrossrefPubMedGoogle Scholar
  • 15 Groussin L, Horvath A, Jullian E, Boikos S, Rene-Corail F, Lefebvre H, Cephise-Velayoudom FL, Vantyghem MC, Chanson P, Conte-Devolx B, Lucas M, Gentil A, Malchoff CD, Tissier F, Carney JA, Bertagna X, Stratakis CA, Bertherat J. A PRKAR1A mutation associated with primary pigmented nodular adrenocortical disease in 12 kindreds. J Clin Endocrinol Metab 2006; 91: 1943-1949
    CrossrefPubMedGoogle Scholar
  • 16 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
    Google Scholar
  • 17 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
    Google Scholar
  • 18 Casey M, Vaughan CJ, He J, Hatcher CJ, Winter JM, Weremowicz S, Montgomery K, Kucherlapati R, Morton CC, Basson CT. Mutations in the protein kinase A R1alpha regulatory subunit cause familial cardiac myxomas and Carney complex. J Clin Invest 2000; 106: R31-R38
    CrossrefPubMedGoogle Scholar
  • 19 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 LS, Bertagna X, Carney JA, Stratakis CA. Mutations in regulatory subunit type 1 A 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
    CrossrefPubMedGoogle Scholar
  • 20 Zawadzki KM, Taylor SS. cAMP-dependent protein kinase regulatory subunit type IIbeta: active site mutations define an isoform-specific network for allosteric signaling by cAMP. J Biol Chem 2004; 279: 7029-7036
    PubMedGoogle Scholar
  • 21 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
    CrossrefPubMedGoogle Scholar
  • 22 Horvath A, Bertherat J, Groussin L, Guillaud-Bataille M, Tsang K, Cazabat L, Libe R, Remmers E, Rene-Corail F, Faucz FR, Clauser E, Calender A, Bertagna X, Carney JA, Stratakis CA. 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
    CrossrefPubMedGoogle Scholar
  • 23 Sandrini F, Stratakis C. Clinical and molecular genetics of Carney complex. Mol Genet Metab 2003; 78: 83-92
    CrossrefPubMedGoogle Scholar
  • 24 Greene EL, Horvath AD, Nesterova M, Giatzakis C, Bossis I, Stratakis CA. In vitro functional studies of naturally occurring pathogenic PRKAR1A mutations that are not subject to nonsense mRNA decay. Hum Mutat 2008; 29: 633-639
    Google Scholar
  • 25 Meoli E, Bossis I, Cazabat L, Mavrakis M, Horvath A, Stergiopoulos S, Shiferaw ML, Fumey G, Perlemoine K, Muchow M, Robinson-White A, Weinberg F, Nesterova M, Patronas Y, Groussin L, Bertherat J, Stratakis CA. Protein kinase A effects of an expressed PRKAR1A mutation associated with aggressive tumors. Cancer Res 2008; 68: 3133-3141
    Google Scholar
  • 26 Groussin L, Kirschner LS, Vincent-Dejean C, Perlemoine K, Jullian E, Delemer B, Zacharieva S, Pignatelli D, Carney JA, Luton JP, Bertagna X, Stratakis CA, 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
    CrossrefPubMedGoogle Scholar
  • 27 Blyth M, Huang S, Maloney V, Crolla JA, Karen Temple IA. 2.3Mb deletion of 17q24.2-q24.3 associated with ‘Carney Complex plus’. Eur J Med Genet 2008; 51: 672-678
    CrossrefPubMedGoogle Scholar
  • 28 Horvath A, Bossis I, Giatzakis C, Levine E, Weinberg F, Meoli E, Robinson-White A, Siegel J, Soni P, Groussin L, Matyakhina L, Verma S, Remmers E, Nesterova M, Carney JA, Bertherat J, Stratakis CA. Large deletions of the PRKAR1A gene in Carney complex. Clin Cancer Res 2008; 14: 388-395
    CrossrefPubMedGoogle Scholar
  • 29 Patronas Y, Horvath A, Greene E, Tsang K, Bimpaki E, Haran M, Nesterova M, Stratakis CA. In Vitro Studies of Novel PRKAR1A Mutants that Extend the Predicted RIalpha Protein Sequence into the 3'-Untranslated Open Reading Frame: Proteasomal Degradation Leads to RIalpha Haploinsufficiency and Carney Complex. J Clin Endocrinol Metab 2012; 97: E496-E502
    CrossrefPubMedGoogle Scholar
  • 30 Vezzosi D, Vignaux O, Dupin N, Bertherat J. Carney complex: Clinical and genetic 2010 update. Ann Endocrinol (Paris). 2010 71. 486-493
    PubMedGoogle Scholar
  • 31 Pereira AM, Hes FJ, Horvath A, Woortman S, Greene E, Bimpaki E, Alatsatianos A, Boikos S, Smit JW, Romijn JA, Nesterova M, Stratakis CA. Association of the M1V PRKAR1A mutation with primary pigmented nodular adrenocortical disease in two large families. J Clin Endocrinol Metab 2010; 95: 338-342
    CrossrefPubMedGoogle Scholar
  • 32 Bertherat J, Groussin L, Sandrini F, Matyakhina L, Bei T, Stergiopoulos S, Papageorgiou T, Bourdeau I, Kirschner LS, Vincent-Dejean C, Perlemoine K, Gicquel C, Bertagna X, Stratakis CA. 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
    Google Scholar
  • 33 Kirschner LS.. PRKAR1A and the evolution of pituitary tumors. Mol Cell Endocrinol 2010; 326: 3-7
    CrossrefPubMedGoogle Scholar
  • 34 Takano K, Yasufuku-Takano J, Morita K, Mori S, Takei M, Osamura RY, Teramoto A, Fujita T. Evidence that PKA activity is constitutively activated in human GH-secreting adenoma cells in a patient with Carney complex harbouring a PRKAR1A mutation. Clin Endocrinol (Oxf) 2009; 70: 769-775
    CrossrefPubMedGoogle Scholar
  • 35 Lania AG, Mantovani G, Ferrero S, Pellegrini C, Bondioni S, Peverelli E, Braidotti P, Locatelli M, Zavanone ML, Ferrante E, Bosari S, Beck-Peccoz P, Spada A. Proliferation of transformed somatotroph cells related to low or absent expression of protein kinase a regulatory subunit 1A protein. Cancer Res 2004; 64: 9193-9198
    CrossrefPubMedGoogle Scholar
  • 36 Mantovani G, Bondioni S, Ferrero S, Gamba B, Ferrante E, Peverelli E, Corbetta S, Locatelli M, Rampini P, Beck-Peccoz P, Spada A, Lania AG. Effect of cyclic adenosine 3′,5′-monophosphate/protein kinase a pathway on markers of cell proliferation in nonfunctioning pituitary adenomas. J Clin Endocrinol Metab 2005; 90: 6721-6724
    CrossrefPubMedGoogle Scholar
  • 37 Sandrini F, Matyakhina L, Sarlis NJ, Kirschner LS, Farmakidis C, Gimm O, Stratakis CA. Regulatory subunit type I-alpha of protein kinase A (PRKAR1A): a tumor-suppressor gene for sporadic thyroid cancer. Genes Chromosomes Cancer 2002; 35: 182-192
    CrossrefPubMedGoogle Scholar
  • 38 Gaujoux S, Tissier F, Ragazzon B, Rebours V, Saloustros E, Perlemoine K, Vincent-Dejean C, Meurette G, Cassagnau E, Dousset B, Bertagna X, Horvath A, Terris B, Carney JA, Stratakis CA, Bertherat J. Pancreatic ductal and acinar cell neoplasms in Carney complex: a possible new association. J Clin Endocrinol Metab 2011; 96: E1888-E1895
    CrossrefPubMedGoogle Scholar
  • 39 Rohlff C, Clair T, Cho-Chung YS. 8-Cl-cAMP induces truncation and down-regulation of the RI alpha subunit and up-regulation of the RII beta subunit of cAMP-dependent protein kinase leading to type II holoenzyme-dependent growth inhibition and differentiation of HL-60 leukemia cells. J Biol Chem 1993; 268: 5774-5782
    PubMedGoogle Scholar
  • 40 Bossis I, Stratakis CA. Minireview: PRKAR1A: normal and abnormal functions. Endocrinology 2004; 145: 5452-5458
    Google Scholar
  • 41 Neary CL, Nesterova M, Cho YS, Cheadle C, Becker KG, Cho-Chung YS. Protein kinase A isozyme switching: eliciting differential cAMP signaling and tumor reversion. Oncogene 2004; 23: 8847-8856
    CrossrefPubMedGoogle Scholar
  • 42 Griffin KJ, Kirschner LS, Matyakhina L, Stergiopoulos SG, Robinson-White A, Lenherr SM, Weinberg FD, Claflin ES, Batista D, Bourdeau I, Voutetakis A, Sandrini F, Meoli EM, Bauer AJ, Cho-Chung YS, Bornstein SR, Carney JA, Stratakis CA. 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
    CrossrefPubMedGoogle Scholar
  • 43 Vincent-Dejean C, Cazabat L, Groussin L, Perlemoine K, Fumey G, Tissier F, Bertagna X, Bertherat J. Identification of a clinically homogenous subgroup of benign cortisol-secreting adrenocortical tumors characterized by alterations of the protein kinase A (PKA) subunits and high PKA activity. Eur J Endocrinol 2008; 158: 829-839
    CrossrefPubMedGoogle Scholar
  • 44 Mantovani G, Lania AG, Bondioni S, Peverelli E, Pedroni C, Ferrero S, Pellegrini C, Vicentini L, Arnaldi G, Bosari S, Beck-Peccoz P, Spada A. Different expression of protein kinase A (PKA) regulatory subunits in cortisol-secreting adrenocortical tumors: relationship with cell proliferation. Exp Cell Res 2008; 314: 123-130
    Google Scholar
  • 45 Lignitto L, Sepe M, Carlucci A, Feliciello A. An intimate connection between ubiquitination and compartmentalized cAMP signaling. Cell Cycle 2011; 10: 2051-2052
    CrossrefPubMedGoogle Scholar
  • 46 Yin Z, Pringle DR, Jones GN, Kelly KM, Kirschner LS. Differential Role of PKA Catalytic Subunits in Mediating Phenotypes Caused by Knockout of the Carney Complex Gene Prkar1a. Mol Endocrinol 2011; 25: 1786-1793
    CrossrefPubMedGoogle Scholar
  • 47 Amieux PS, Howe DG, Knickerbocker H, Lee DC, Su T, Laszlo GS, Idzerda RL, McKnight GS. Increased basal cAMP-dependent protein kinase activity inhibits the formation of mesoderm-derived structures in the developing mouse embryo. J Biol Chem 2002; 277: 27294-27304
    CrossrefPubMedGoogle Scholar
  • 48 Griffin KJ, Kirschner LS, Matyakhina L, Stergiopoulos S, Robinson-White A, Lenherr S, Weinberg FD, Claflin E, Meoli E, Cho-Chung YS, Stratakis CA. Down-regulation of regulatory subunit type 1A of protein kinase A leads to endocrine and other tumors. Cancer Res 2004; 64: 8811-8815
    CrossrefPubMedGoogle Scholar
  • 49 Kirschner LS, Kusewitt DF, Matyakhina L, Towns 2nd WH, Carney JA, Westphal H, Stratakis CA. A mouse model for the Carney complex tumor syndrome develops neoplasia in cyclic AMP-responsive tissues. Cancer Res 2005; 65: 4506-4514
    CrossrefPubMedGoogle Scholar
  • 50 Yin Z, Williams-Simons L, Parlow AF, Asa S, Kirschner LS. Pituitary-specific knockout of the Carney complex gene Prkar1a leads to pituitary tumorigenesis. Mol Endocrinol 2008; 22: 380-387
    PubMedGoogle Scholar
  • 51 Yin Z, Jones GN, Towns 2nd WH, Zhang X, Abel ED, Binkley PF, Jarjoura D, Kirschner LS. Heart-specific ablation of Prkar1a causes failure of heart development and myxomagenesis. Circulation 2008; 117: 1414-1422
    CrossrefPubMedGoogle Scholar
  • 52 Nadella KS, Kirschner LS. Disruption of protein kinase a regulation causes immortalization and dysregulation of D-type cyclins. Cancer Res 2005; 65: 10307-10315
    CrossrefPubMedGoogle Scholar
  • 53 Lambert-Langlais S, Val P, Guyot S, Ragazzon B, Sahut-Barnola I, De Haze A, Lefrancois-Martinez AM, Martinez A. A transgenic mouse line with specific Cre recombinase expression in the adrenal cortex. Mol Cell Endocrinol 2009; 300: 197-204
    CrossrefPubMedGoogle Scholar
  • 54 Horvath A, Mathyakina L, Vong Q, Baxendale V, Pang AL, Chan WY, Stratakis CA. Serial analysis of gene expression in adrenocortical hyperplasia caused by a germline PRKAR1A mutation. J Clin Endocrinol Metab 2006; 91: 584-596
    CrossrefPubMedGoogle Scholar
  • 55 Gupte RS, Pozarowski P, Grabarek J, Traganos F, Darzynkiewicz Z, Lee MY. RIalpha influences cellular proliferation in cancer cells by transporting RFC40 into the nucleus. Cancer Biol Ther 2005; 4: 429-437
    CrossrefPubMedGoogle Scholar
  • 56 Moujalled D, Weston R, Anderton H, Ninnis R, Goel P, Coley A, Huang DC, Wu L, Strasser A, Puthalakath H. Cyclic-AMP-dependent protein kinase A regulates apoptosis by stabilizing the BH3-only protein Bim. EMBO Rep 2011; 12: 77-83
    CrossrefPubMedGoogle Scholar
  • 57 Tortora G, Pepe S, Cirafici AM, Ciardiello F, Porcellini A, Clair T, Colletta G, Cho-Chung YS, Bianco AR. Thyroid-stimulating hormone-regulated growth and cell cycle distribution of thyroid cells involve type I isozyme of cyclic AMP-dependent protein kinase. Cell Growth Differ 1993; 4: 359-365
    PubMedGoogle Scholar
  • 58 Yokozaki H, Budillon A, Tortora G, Meissner S, Beaucage SL, Miki K, Cho-Chung YS. An antisense oligodeoxynucleotide that depletes RI alpha subunit of cyclic AMP-dependent protein kinase induces growth inhibition in human cancer cells. Cancer Res 1993; 53: 868-872
    PubMedGoogle Scholar
  • 59 Robinson-White A, Hundley TR, Shiferaw M, Bertherat J, Sandrini F, Stratakis CA. Protein kinase-A activity in PRKAR1A-mutant cells, and regulation of mitogen-activated protein kinases ERK1/2. Hum Mol Genet 2003; 12: 1475-1484
    CrossrefPubMedGoogle Scholar
  • 60 Robinson-White A, Meoli E, Stergiopoulos S, Horvath A, Boikos S, Bossis I, Stratakis CA. PRKAR1A Mutations and protein kinase A interactions with other signaling pathways in the adrenal cortex. J Clin Endocrinol Metab 2006; 91: 2380-2388
    CrossrefPubMedGoogle Scholar
  • 61 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
    CrossrefPubMedGoogle Scholar
  • 62 Bouizar Z, Ragazzon B, Viou L, Hortane M, Bertherat J, Rizk-Rabin M. 8Cl-cAMP modifies the balance between PKAR1 and PKAR2 and modulates the cell cycle, growth and apoptosis in human adrenocortical H295R cells. J Mol Endocrinol 2010; 44: 331-347
    CrossrefPubMedGoogle Scholar
  • 63 Schreyer SA, Cummings DE, McKnight GS, LeBoeuf RC. Mutation of the RIIbeta subunit of protein kinase A prevents diet-induced insulin resistance and dyslipidemia in mice. Diabetes 2001; 50: 2555-2562
    CrossrefPubMedGoogle Scholar
  • 64 Enns LC, Morton JF, Treuting PR, Emond MJ, Wolf NS, Dai DF, McKnight GS, Rabinovitch PS, Ladiges WC. Disruption of protein kinase A in mice enhances healthy aging. PLoS One 2009; 4: e5963
    CrossrefPubMedGoogle Scholar
  • 65 Nadella KS, Saji M, Jacob NK, Pavel E, Ringel MD, Kirschner LS. Regulation of actin function by protein kinase A-mediated phosphorylation of Limk1. EMBO Rep 2009; 10: 599-605
    CrossrefPubMedGoogle Scholar
  • 66 Brunk UT, Terman A. Lipofuscin: mechanisms of age-related accumulation and influence on cell function. Free Radic Biol Med 2002; 33: 611-619
    CrossrefPubMedGoogle Scholar
  • 67 Mavrakis M, Lippincott-Schwartz J, Stratakis CA, 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
    CrossrefPubMedGoogle Scholar
  • 68 Nadella KS, Jones GN, Trimboli A, Stratakis CA, Leone G, Kirschner LS. Targeted deletion of Prkar1a reveals a role for protein kinase A in mesenchymal-to-epithelial transition. Cancer Res 2008; 68: 2671-2677
    CrossrefPubMedGoogle Scholar
  • 69 Tadjine M, Lampron A, Ouadi L, Horvath A, Stratakis CA, Bourdeau I. Detection of somatic beta-catenin mutations in primary pigmented nodular adrenocortical disease (PPNAD). Clin Endocrinol (Oxf) 2008; 69: 367-373
    CrossrefPubMedGoogle Scholar
  • 70 Roy L, McDonald CA, Jiang C, Maroni D, Zeleznik AJ, Wyatt TA, Hou X, Davis JS. 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
    CrossrefPubMedGoogle Scholar
  • 71 Bourdeau I, Antonini SR, Lacroix A, Kirschner LS, Matyakhina L, Lorang D, Libutti SK, Stratakis CA. Gene array analysis of macronodular adrenal hyperplasia confirms clinical heterogeneity and identifies several candidate genes as molecular mediators. Oncogene 2004; 23: 1575-1585
    CrossrefPubMedGoogle Scholar
  • 72 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
    CrossrefPubMedGoogle Scholar
  • 73 Iliopoulos D, Bimpaki EI, Nesterova M, Stratakis CA. MicroRNA signature of primary pigmented nodular adrenocortical disease: clinical correlations and regulation of Wnt signaling. Cancer Res 2009; 69: 3278-3282
    CrossrefPubMedGoogle Scholar
  • 74 Robinson-White AJ, Hsiao HP, Leitner WW, Greene E, Bauer A, Krett NL, Nesterova M, Stratakis CA. Protein kinase A-independent inhibition of proliferation and induction of apoptosis in human thyroid cancer cells by 8-Cl-adenosine. J Clin Endocrinol Metab 2008; 93: 1020-1029
    PubMedGoogle Scholar
  • 75 Robinson-White AJ, Bossis I, Hsiao HP, Nesterova M, Leitner WW, Stratakis CA. 8-Cl-adenosine inhibits proliferation and causes apoptosis in B-lymphocytes via protein kinase A-dependent and independent effects: implications for treatment of Carney complex-associated tumors. J Clin Endocrinol Metab 2009; 94: 4061-4069
    CrossrefPubMedGoogle Scholar