title: Differential role of PKA catalytic subunits in mediating phenotypes caused by knockout of the Carney complex gene Prkar1a.
abstract: The Carney complex is an inherited tumor predisposition caused by activation of the cAMP-dependent protein kinase [protein kinase A (PKA)] resulting from mutation of the PKA-regulatory subunit gene PRKAR1A. Myxomas and tumors in cAMP-responsive tissues are cardinal features of this syndrome, which is unsurprising given the important role played by PKA in modulating cell growth and function. Previous studies demonstrated that cardiac-specific knockout of Prkar1a causes embryonic heart failure and myxomatous degeneration in the heart, whereas limited Schwann cell-specific knockout of the gene causes schwannoma formation. In this study, we sought to determine the role of PKA activation in this phenotype by using genetic means to reduce PKA enzymatic activity. To accomplish this goal, we introduced null alleles of the PKA catalytic subunits Prkaca (Ca) or Prkacb (Cb) into the Prkar1a-cardiac knockout (R1a-CKO) or limited Schwann cell knockout (R1a-TEC3KO) line. Heterozygosity for Prkaca rescued the embryonic lethality of the R1a-CKO, although mice had a shorter than normal lifespan and died from cardiac failure with atrial thrombosis. In contrast, heterozygosity for Prkacb only enabled the mice to survive 1 extra day during embryogenesis. Biochemical analysis indicated that reduction of Ca markedly reduced PKA activity in embryonic hearts, whereas reduction of Cb had minimal effects. In R1a-TEC3KO mice, tumorigenesis was completely suppressed by a heterozygosity for Prkaca, and by more than 80% by heterozygosity for Prkacb. These data suggest that both developmental and tumor phenotypes caused by Prkar1a mutation result from excess PKA activity due to PKA-Ca.
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics, Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Yin
authors.forename: Daphne R
authors.initials: DR
authors.lastname: Pringle
authors.forename: Georgette N
authors.initials: GN
authors.lastname: Jones
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: Kelly
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Kirschner
mesh_terms: D000375:Aging / Q000473:pathology; D000818:Animals; D056733:Carney Complex / Q000150:complications / Q000201:enzymology* / Q000473:pathology*; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / Q000172:deficiency / Q000378:metabolism*; D020964:Embryo Loss / Q000473:pathology; D017353:Gene Deletion; D006321:Heart / Q000196:embryology / Q000503:physiopathology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D016019:Survival Analysis
chemical_list: D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits; C517758:Prkaca protein, mouse; C517761:Prkacb protein, mouse