Cushing's Syndrome and Fetal Features Resurgence in Adrenal Cortex–Specific Knockout Mice
Carney complex (CNC) is an inherited neoplasia syndrome with endocrine overactivity. Its most frequent endocrine manifestation is primary pigmented nodular adrenocortical disease (PPNAD), a bilateral adrenocortical hyperplasia causing pituitary-independent Cushing's syndrome. Inactivating mutations in PRKAR1A, a gene encoding the type 1 α-regulatory subunit (R1α) of the cAMP–dependent protein kinase (PKA) have been found in 80% of CNC patients with Cushing's syndrome. To demonstrate the implication of R1α loss in the initiation and development of PPNAD, we generated mice lacking Prkar1a specifically in the adrenal cortex (AdKO). AdKO mice develop pituitary-independent Cushing's syndrome with increased PKA activity. This leads to autonomous steroidogenic genes expression and deregulated adreno-cortical cells differentiation, increased proliferation and resistance to apoptosis. Unexpectedly, R1α loss results in improper maintenance and centrifugal expansion of cortisol-producing fetal adrenocortical cells with concomitant regression of adult cortex. Our data provide the first in vivo evidence that loss of R1α is sufficient to induce autonomous adrenal hyper-activity and bilateral hyperplasia, both observed in human PPNAD. Furthermore, this model demonstrates that deregulated PKA activity favors the emergence of a new cell population potentially arising from the fetal adrenal, giving new insight into the mechanisms leading to PPNAD.
Vyšlo v časopise:
Cushing's Syndrome and Fetal Features Resurgence in Adrenal Cortex–Specific Knockout Mice. PLoS Genet 6(6): e32767. doi:10.1371/journal.pgen.1000980
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1000980
Souhrn
Carney complex (CNC) is an inherited neoplasia syndrome with endocrine overactivity. Its most frequent endocrine manifestation is primary pigmented nodular adrenocortical disease (PPNAD), a bilateral adrenocortical hyperplasia causing pituitary-independent Cushing's syndrome. Inactivating mutations in PRKAR1A, a gene encoding the type 1 α-regulatory subunit (R1α) of the cAMP–dependent protein kinase (PKA) have been found in 80% of CNC patients with Cushing's syndrome. To demonstrate the implication of R1α loss in the initiation and development of PPNAD, we generated mice lacking Prkar1a specifically in the adrenal cortex (AdKO). AdKO mice develop pituitary-independent Cushing's syndrome with increased PKA activity. This leads to autonomous steroidogenic genes expression and deregulated adreno-cortical cells differentiation, increased proliferation and resistance to apoptosis. Unexpectedly, R1α loss results in improper maintenance and centrifugal expansion of cortisol-producing fetal adrenocortical cells with concomitant regression of adult cortex. Our data provide the first in vivo evidence that loss of R1α is sufficient to induce autonomous adrenal hyper-activity and bilateral hyperplasia, both observed in human PPNAD. Furthermore, this model demonstrates that deregulated PKA activity favors the emergence of a new cell population potentially arising from the fetal adrenal, giving new insight into the mechanisms leading to PPNAD.
Zdroje
1. CarneyJA
GordonH
CarpenterPC
ShenoyBV
GoVL
1985 The complex of myxomas, spotty pigmentation, and endocrine overactivity. Medicine (Baltimore) 64 270 283
2. KirschnerLS
CarneyJA
PackSD
TaymansSE
GiatzakisC
2000 Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex. Nat Genet 26 89 92
3. CaseyM
VaughanCJ
HeJ
HatcherCJ
WinterJM
2000 Mutations in the protein kinase A R1alpha regulatory subunit cause familial cardiac myxomas and Carney complex. J Clin Invest 106 R31 38
4. GroussinL
JullianE
PerlemoineK
LouvelA
LeheupB
2002 Mutations of the PRKAR1A gene in Cushing's syndrome due to sporadic primary pigmented nodular adrenocortical disease. J Clin Endocrinol Metab 87 4324 4329
5. AmieuxPS
HoweDG
KnickerbockerH
LeeDC
SuT
2002 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
6. KirschnerLS
KusewittDF
MatyakhinaL
TownsWH2nd
CarneyJA
2005 A mouse model for the Carney complex tumor syndrome develops neoplasia in cyclic AMP-responsive tissues. Cancer Res 65 4506 4514
7. VeugelersM
WilkesD
BurtonK
McDermottDA
SongY
2004 Comparative PRKAR1A genotype-phenotype analyses in humans with Carney complex and prkar1a haploinsufficient mice. Proc Natl Acad Sci U S A 101 14222 14227
8. GriffinKJ
KirschnerLS
MatyakhinaL
StergiopoulosSG
Robinson-WhiteA
2004 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 41 923 931
9. YinZ
JonesGN
TownsWH2nd
ZhangX
AbelED
2008 Heart-specific ablation of Prkar1a causes failure of heart development and myxomagenesis. Circulation 117 1414 1422
10. YinZ
Williams-SimonsL
ParlowAF
AsaS
KirschnerLS
2008 Pituitary-specific knockout of the Carney complex gene Prkar1a leads to pituitary tumorigenesis. Mol Endocrinol 22 380 387
11. JonesGN
TepC
TownsWH2nd
MihaiG
TonksID
2008 Tissue-specific ablation of Prkar1a causes schwannomas by suppressing neurofibromatosis protein production. Neoplasia 10 1213 1221
12. BertheratJ
HorvathA
GroussinL
GrabarS
BoikosS
2009 Mutations in regulatory subunit type 1A of cyclic AMP-dependent protein kinase (PRKAR1A): phenotype analysis in 353 patients and 80 different genotypes. J Clin Endocrinol Metab
13. Lambert-LanglaisS
ValP
GuyotS
RagazzonB
Sahut-BarnolaI
2009 A transgenic mouse line with specific Cre recombinase expression in the adrenal cortex. Mol Cell Endocrinol 300 197 204
14. KimAC
HammerGD
2007 Adrenocortical cells with stem/progenitor cell properties: recent advances. Mol Cell Endocrinol 265-266 10 16
15. ParviainenH
KiiveriS
BielinskaM
RahmanN
HuhtaniemiIT
2007 GATA transcription factors in adrenal development and tumors. Mol Cell Endocrinol 265-266 17 22
16. KingP
PaulA
LauferE
2009 Shh signaling regulates adrenocortical development and identifies progenitors of steroidogenic lineages. Proc Natl Acad Sci U S A 106 21185 21190
17. KimAC
BarlaskarFM
HeatonJH
ElseT
KellyVR
2009 In search of adrenocortical stem and progenitor cells. Endocr Rev 30 241 263
18. KimAC
ReuterAL
ZubairM
ElseT
SereckyK
2008 Targeted disruption of beta-catenin in Sf1-expressing cells impairs development and maintenance of the adrenal cortex. Development 135 2593 2602
19. ThomasM
KeramidasM
MonchauxE
FeigeJJ
2004 Dual hormonal regulation of endocrine tissue mass and vasculature by adrenocorticotropin in the adrenal cortex. Endocrinology 145 4320 4329
20. SpencerSJ
MesianoS
LeeJY
JaffeRB
1999 Proliferation and apoptosis in the human adrenal cortex during the fetal and perinatal periods: implications for growth and remodeling. J Clin Endocrinol Metab 84 1110 1115
21. BeuschleinF
LooyengaBD
BleasdaleSE
MutchC
BaversDL
2003 Activin induces x-zone apoptosis that inhibits luteinizing hormone-dependent adrenocortical tumor formation in inhibin-deficient mice. Mol Cell Biol 23 3951 3964
22. ChenYG
LuiHM
LinSL
LeeJM
YingSY
2002 Regulation of cell proliferation, apoptosis, and carcinogenesis by activin. Exp Biol Med (Maywood) 227 75 87
23. HolmesPV
DicksonAD
1971 X-zone degeneration in the adrenal glands of adult and immature female mice. J Anat 108 159 168
24. ZubairM
ParkerKL
MorohashiK
2008 Developmental links between the fetal and adult zones of the adrenal cortex revealed by lineage tracing. Mol Cell Biol 28 7030 7040
25. AigueperseC
MartinezA
Lefrancois-MartinezAM
VeyssiereG
JeanCI
1999 Cyclic AMP regulates expression of the gene coding for a mouse vas deferens protein related to the aldo-keto reductase superfamily in human and murine adrenocortical cells. J Endocrinol 160 147 154
26. HershkovitzL
BeuschleinF
KlammerS
KrupM
WeinsteinY
2007 Adrenal 20alpha-hydroxysteroid dehydrogenase in the mouse catabolizes progesterone and 11-deoxycorticosterone and is restricted to the X-zone. Endocrinology 148 976 988
27. KeeneyDS
JenkinsCM
WatermanMR
1995 Developmentally regulated expression of adrenal 17 alpha-hydroxylase cytochrome P450 in the mouse embryo. Endocrinology 136 4872 4879
28. Gomez MuguruzaMT
ChrousosGP
1989 Periodic Cushing syndrome in a short boy: usefulness of the ovine corticotropin releasing hormone test. J Pediatr 115 270 273
29. SarlisNJ
ChrousosGP
DoppmanJL
CarneyJA
StratakisCA
1997 Primary pigmented nodular adrenocortical disease: reevaluation of a patient with carney complex 27 years after unilateral adrenalectomy. J Clin Endocrinol Metab 82 1274 1278
30. StratakisCA
SarlisN
KirschnerLS
CarneyJA
DoppmanJL
1999 Paradoxical response to dexamethasone in the diagnosis of primary pigmented nodular adrenocortical disease. Ann Intern Med 131 585 591
31. BourdeauI
LacroixA
SchurchW
CaronP
AntaklyT
2003 Primary pigmented nodular adrenocortical disease: paradoxical responses of cortisol secretion to dexamethasone occur in vitro and are associated with increased expression of the glucocorticoid receptor. J Clin Endocrinol Metab 88 3931 3937
32. LouisetE
StratakisCA
PerraudinV
GriffinKJ
LibeR
2009 The paradoxical increase in cortisol secretion induced by dexamethasone in primary pigmented nodular adrenocortical disease involves a glucocorticoid receptor-mediated effect of dexamethasone on protein kinase A catalytic subunits. J Clin Endocrinol Metab 94 2406 2413
33. ShenoyBV
CarpenterPC
CarneyJA
1984 Bilateral primary pigmented nodular adrenocortical disease. Rare cause of the Cushing syndrome. Am J Surg Pathol 8 335 344
34. BrunkUT
TermanA
2002 Lipofuscin: mechanisms of age-related accumulation and influence on cell function. Free Radic Biol Med 33 611 619
35. MavrakisM
Lippincott-SchwartzJ
StratakisCA
BossisI
2006 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 15 2962 2971
36. KurzT
TermanA
BrunkUT
2007 Autophagy, ageing and apoptosis: the role of oxidative stress and lysosomal iron. Arch Biochem Biophys 462 220 230
37. MavrakisM
Lippincott-SchwartzJ
StratakisCA
BossisI
2007 mTOR kinase and the regulatory subunit of protein kinase A (PRKAR1A) spatially and functionally interact during autophagosome maturation. Autophagy 3 151 153
38. RuvinskyI
MeyuhasO
2006 Ribosomal protein S6 phosphorylation: from protein synthesis to cell size. Trends Biochem Sci 31 342 348
39. TaylorSS
BuechlerJA
YonemotoW
1990 cAMP-dependent protein kinase: framework for a diverse family of regulatory enzymes. Annu Rev Biochem 59 971 1005
40. NadellaKS
KirschnerLS
2005 Disruption of protein kinase a regulation causes immortalization and dysregulation of D-type cyclins. Cancer Res 65 10307 10315
41. HorvathA
MathyakinaL
VongQ
BaxendaleV
PangAL
2006 Serial analysis of gene expression in adrenocortical hyperplasia caused by a germline PRKAR1A mutation. J Clin Endocrinol Metab 91 584 596
42. IseliBE
HedingerCE
1985 Histopathology and ultrastructure of primary adrenocortical nodular dysplasia with Cushing's syndrome. Histopathology 9 1171 1194
43. AibaM
HirayamaA
IriH
KodamaT
FujimotoY
1990 Primary adrenocortical micronodular dysplasia: enzyme histochemical and ultrastructural studies of two cases with a review of the literature. Hum Pathol 21 503 511
44. ZubairM
IshiharaS
OkaS
OkumuraK
MorohashiK
2006 Two-step regulation of Ad4BP/SF-1 gene transcription during fetal adrenal development: initiation by a Hox-Pbx1-Prep1 complex and maintenance via autoregulation by Ad4BP/SF-1. Mol Cell Biol 26 4111 4121
45. VoutilainenR
EramaaM
RitvosO
1991 Hormonally regulated inhibin gene expression in human fetal and adult adrenals. J Clin Endocrinol Metab 73 1026 1030
46. RagazzonB
CazabatL
Rizk-RabinM
AssieG
GroussinL
2009 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 69 7278 7284
47. SpencerSJ
RabinoviciJ
MesianoS
GoldsmithPC
JaffeRB
1992 Activin and inhibin in the human adrenal gland. Regulation and differential effects in fetal and adult cells. J Clin Invest 90 142 149
48. ItoM
ParkY
WeckJ
MayoKE
JamesonJL
2000 Synergistic activation of the inhibin alpha-promoter by steroidogenic factor-1 and cyclic adenosine 3',5'-monophosphate. Mol Endocrinol 14 66 81
49. VanttinenT
KuulasmaaT
LiuJ
VoutilainenR
2002 Expression of activin/inhibin receptor and binding protein genes and regulation of activin/inhibin peptide secretion in human adrenocortical cells. J Clin Endocrinol Metab 87 4257 4263
50. KananenK
MarkkulaM
MikolaM
RainioEM
McNeillyA
1996 Gonadectomy permits adrenocortical tumorigenesis in mice transgenic for the mouse inhibin alpha-subunit promoter/simian virus 40 T-antigen fusion gene: evidence for negative autoregulation of the inhibin alpha-subunit gene. Mol Endocrinol 10 1667 1677
51. FarnworthPG
StantonPG
WangY
EscalonaR
FindlayJK
2006 Inhibins differentially antagonize activin and bone morphogenetic protein action in a mouse adrenocortical cell line. Endocrinology 147 3462 3471
52. GrumbachMM
BillerBM
BraunsteinGD
CampbellKK
CarneyJA
2003 Management of the clinically inapparent adrenal mass (“incidentaloma”). Ann Intern Med 138 424 429
53. HeikkilaM
PeltoketoH
LeppaluotoJ
IlvesM
VuolteenahoO
2002 Wnt-4 deficiency alters mouse adrenal cortex function, reducing aldosterone production. Endocrinology 143 4358 4365
54. BelloniAS
MazzocchiG
MeneghelliV
NussdorferGG
1978 Cytogenesis in the rat adrenal cortex: evidence for an ACTH-induced centripetal cell migration from the zona glomerulosa. Arch Anat Histol Embryol 61 195 205
55. DoghmanM
KarpovaT
RodriguesGA
ArhatteM
De MouraJ
2007 Increased steroidogenic factor-1 dosage triggers adrenocortical cell proliferation and cancer. Mol Endocrinol 21 2968 2987
56. BerthonA
Sahut-BarnolaI
Lambert-LanglaisS
de JoussineauC
Damon-SoubeyrandC
2010 Constitutive {beta}-catenin activation induces adrenal hyperplasia and promotes adrenal cancer development. Hum Mol Genet
57. LooyengaBD
WiaterE
ValeW
HammerGD
2010 Inhibin-A antagonizes TGFbeta2 signaling by down-regulating cell surface expression of the TGFbeta coreceptor betaglycan. Mol Endocrinol 24 608 620
58. LiuJ
MatyakhinaL
HanZ
SandriniF
BeiT
2003 Molecular cloning, chromosomal localization of human peripheral-type benzodiazepine receptor and PKA regulatory subunit type 1A (PRKAR1A)-associated protein PAP7, and studies in PRKAR1A mutant cells and tissues. Faseb J 17 1189 1191
59. Lefrancois-MartinezAM
BertheratJ
ValP
TournaireC
Gallo-PayetN
2004 Decreased expression of cyclic adenosine monophosphate-regulated aldose reductase (AKR1B1) is associated with malignancy in human sporadic adrenocortical tumors. J Clin Endocrinol Metab 89 3010 3019
60. RagazzonB
Lefrancois-MartinezAM
ValP
Sahut-BarnolaI
TournaireC
2006 Adrenocorticotropin-dependent changes in SF-1/DAX-1 ratio influence steroidogenic genes expression in a novel model of glucocorticoid-producing adrenocortical cell lines derived from targeted tumorigenesis. Endocrinology 147 1805 1818
61. GroussinL
HorvathA
JullianE
BoikosS
Rene-CorailF
2006 A PRKAR1A mutation associated with primary pigmented nodular adrenocortical disease in 12 kindreds. J Clin Endocrinol Metab 91 1943 1949
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