Document Detail

Cushing's syndrome and fetal features resurgence in adrenal cortex-specific Prkar1a knockout mice.
MedLine Citation:
PMID:  20548949     Owner:  NLM     Status:  MEDLINE    
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 alpha-regulatory subunit (R1alpha) of the cAMP-dependent protein kinase (PKA) have been found in 80% of CNC patients with Cushing's syndrome. To demonstrate the implication of R1alpha 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, R1alpha 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 R1alpha 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.
Isabelle Sahut-Barnola; Cyrille de Joussineau; Pierre Val; Sarah Lambert-Langlais; Christelle Damon; Anne-Marie Lefrançois-Martinez; Jean-Christophe Pointud; Geoffroy Marceau; Vincent Sapin; Frédérique Tissier; Bruno Ragazzon; Jérôme Bertherat; Lawrence S Kirschner; Constantine A Stratakis; Antoine Martinez
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-06-10
Journal Detail:
Title:  PLoS genetics     Volume:  6     ISSN:  1553-7404     ISO Abbreviation:  PLoS Genet.     Publication Date:  2010 Jun 
Date Detail:
Created Date:  2010-06-15     Completed Date:  2010-09-27     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  101239074     Medline TA:  PLoS Genet     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e1000980     Citation Subset:  IM    
CNRS UMR6247, Génétique Reproduction et Développement, Clermont Université, Aubière, France.
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MeSH Terms
Adrenal Cortex / metabolism*
Adrenocorticotropic Hormone / metabolism
Cell Proliferation
Cushing Syndrome / embryology,  genetics,  metabolism*,  pathology
Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / deficiency,  metabolism*
Cyclic AMP-Dependent Protein Kinases / metabolism
Mice, Knockout
Signal Transduction
Steroid 17-alpha-Hydroxylase / metabolism
Reg. No./Substance:
0/Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; 0/Prkar1a protein, mouse; 9002-60-2/Adrenocorticotropic Hormone; EC 17-alpha-Hydroxylase; EC AMP-Dependent Protein Kinases

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