PRKAR1A inactivation leads to increased proliferation and decreased apoptosis in human B lymphocytes.
The multiple neoplasia syndrome Carney complex (CNC) is caused by heterozygote mutations in the gene, which codes for the RIalpha regulatory subunit (PRKAR1A) of protein kinase A. Inactivation of PRKAR1A and the additional loss of the normal allele lead to tumors in CNC patients and increased cyclic AMP signaling in their cells, but the oncogenetic mechanisms in affected tissues remain unknown. Previous studies suggested that PRKAR1A down-regulation may lead to increased mitogen-activated protein kinase (MAPK) signaling. Here, we show that, in lymphocytes with PRKAR1A-inactivating mutations, there is increased extracellular signal-regulated kinase (ERK) 1/2 and B-raf phosphorylation and MAPK/ERK kinase 1/2 and c-Myc activation, whereas c-Raf-1 is inhibited. These changes are accompanied by increased cell cycle rates and decreased apoptosis that result in an overall net gain in proliferation and survival. In conclusion, inactivation of PRKAR1A leads to widespread changes in molecular pathways that control cell cycle and apoptosis. This is the first study to show that human cells with partially inactivated RIalpha levels have increased proliferation and survival, suggesting that loss of the normal allele in these cells is not necessary for these changes to occur.
Robinson-White
Audrey J
AJ
Section on Endocrinology and Genetics, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, NIH, Bethesda, Maryland 20892, USA.
Leitner
Wolfgang W
WW
Aleem
Eiman
E
Kaldis
Philipp
P
Bossis
Ioannis
I
Stratakis
Constantine A
CA
D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000502:physiology*; D002453:Cell Cycle; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D020935:MAP Kinase Signaling System; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology
D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D005419:Flavonoids; C517834:PRKAR1A protein, human; D016271:Proto-Oncogene Proteins c-myc; D017868:Cyclic AMP-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D007545:Isoproterenol; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one