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Submitted on January 27, 2006
Accepted on March 20, 2006
Section on Endocrinology & Genetics, and Pediatric Endocrinology Training Program, both at the Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
* To whom correspondence should be addressed. E-mail: stratakc{at}mail.nih.gov.
Context: Primary pigmented nodular adrenocortical disease (PPNAD), associated with Carney complex (CNC), is caused by mutations in PRKAR1A (mt-PRKAR1A) a gene that codes for the regulatory subunit type 1-
(RI) of cyclic AMP-dependent protein kinase (PKA). PRKAR1A inactivation is associated with dysregulated PKA activity that is thought to result in tumorigenesis. mt-PRKAR1A-bearing lymphocytes from CNC patients exhibit enhanced cell proliferation associated with increased expression of the mitogen-activated protein kinase (MAPK) ERK1/2 pathway.
Objective: To determine how PKA and its subunits and ERK1/2 and their molecular partners change in the presence of PRKAR1A mutations in adrenocortical tissue.
Design: PKA activity and subunit expression, ERK1/2, and other immunoassays, and immunohistochemistry on adrenocortical samples from patients with germline normal or mt-PRKAR1A.
Results: Increased cAMP-stimulated total kinase activity was associated with mt-PRKAR1A. PKA subunit expression analysis in mt-PRKAR1A tissues, by quantitative mRNA assay and immunoblotting, showed a 2.4-fold (P = 0.02) and 1.8-fold (P = 0.09) decrease in RI's message and protein, respectively, and increases in other PKA subunits. Immunoassays showed 2- (P = 0.03) and 6-fold (P = 0.03) decreases in baseline ERK1/2, with corresponding increases in phosphorylated (p) ERK1/2 in mt-PRKAR1A samples. B-raf kinase, p-MEK1/2 and p-c-Myc, but not p-Akt/PKB, were significantly increased. Immunohistochemistry studies supported these data.
Conclusions: mt-PRKAR1A causes increased total cAMP-stimulated kinase activity, likely the result of up-regulation of other PKA subunits caused by RI's down-regulation, as seen in human lymphocytes and mouse animal models. These changes, associated with enhanced MAPK activity may be, in part, responsible for the proliferative signals that result in PPNAD formation.
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cyclic AMP •
Carney complex •
ERK1/2 •
protein kinase B
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