title: Comparison of the effects of PRKAR1A and PRKAR2B depletion on signaling pathways, cell growth, and cell cycle control of adrenocortical cells.
abstract: The cyclic AMP/protein kinase A signaling cascade is one of the main pathways involved in the pathogenesis of adrenocortical tumors. The PKA R1A and R2B proteins are the most abundant regulatory subunits in endocrine tissues. Inactivating mutations of PRKAR1A are associated with Carney complex and a subset of sporadic tumors and the abundance of R2B protein is low in a subset of secreting adrenocortical adenomas. We previously showed that PRKAR1A and PRKAR2B inactivation have anti-apoptotic effects on the adrenocortical carcinoma cell line H295R. The aim of this study was to compare the effects of PRKAR1A and PRKAR2B depletion on cell proliferation, apoptosis, cell signaling pathways, and cell cycle regulation. We found that PRKAR2B depletion is compensated by an upregulation of R1A protein, whereas PRKAR1A depletion has no effect on the production of R2B. The depletion of either PRKAR1A or PRKAR2B promotes the expression of Bcl-xL and resistance to apoptosis; and is associated with a high percentage of cells in S and G2 phase, activates PKA and MEK/ERK pathways, and impairs the expression of IkB leading to activate the NF-κB pathway. However, we observed differences in the regulation of cyclins. The depletion of PRKAR1A leads to the accumulation of cyclin D1 and p27kip, whereas the depletion of PRKAR2B promotes the accumulation of cyclin A, B, cdk1, cdc2, and p21Cip. In conclusion, although the depletion of PRKAR1A and PRKAR2B in adrenocortical cells has similar effects on cell proliferation and apoptosis; loss of these PKA subunits differentially affects cyclin expression.
authors.affiliation: INSERM U1016, CNRS (UMR 8104), Institut Cochin, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France, Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Basso
authors.affiliation: INSERM U1016, CNRS (UMR 8104), Institut Cochin, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France, Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Rocchetti
authors.affiliation: INSERM U1016, CNRS (UMR 8104), Institut Cochin, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France, Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Rodriguez
authors.affiliation: National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, USA.
authors.forename: M
authors.initials: M
authors.lastname: Nesterova
authors.affiliation: INSERM U1016, CNRS (UMR 8104), Institut Cochin, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France, Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Cormier
authors.affiliation: National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Stratakis
authors.affiliation: INSERM U1016, CNRS (UMR 8104), Institut Cochin, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France, Paris, France.
authors.forename: B
authors.initials: B
authors.lastname: Ragazzon
authors.affiliation: INSERM U1016, CNRS (UMR 8104), Institut Cochin, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France, Paris, France.
authors.forename: J
authors.initials: J
authors.lastname: Bertherat
authors.affiliation: INSERM U1016, CNRS (UMR 8104), Institut Cochin, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Rizk-Rabin
mesh_terms: D000311:Adrenal Glands / Q000166:cytology* / Q000201:enzymology*; D017209:Apoptosis; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000378:metabolism*; D054753:Cyclic AMP-Dependent Protein Kinase RIbeta Subunit / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System; D016328:NF-kappa B / Q000378:metabolism; D021122:Protein Subunits / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D054753:Cyclic AMP-Dependent Protein Kinase RIbeta Subunit; D016213:Cyclins; D016328:NF-kappa B; C517834:PRKAR1A protein, human; C517766:PRKAR1B protein, human; D021122:Protein Subunits; D018844:Cyclin-Dependent Kinases