Targeted deletion of Prkar1a reveals a role for protein kinase A in mesenchymal-to-epithelial transition.
Dysregulation of protein kinase A (PKA) activity, caused by loss of function mutations in PRKAR1A, is known to induce tumor formation in the inherited tumor syndrome Carney complex (CNC) and is also associated with sporadic tumors of the thyroid and adrenal. We have previously shown that Prkar1a(+/-) mice develop schwannomas reminiscent of those seen in CNC and that similar tumors are observed in tissue-specific knockouts (KO) of Prkar1a targeted to the neural crest. Within these tumors, we have previously described the presence of epithelial islands, although the nature of these structures was unclear. In this article, we report that these epithelial structures are derived from KO cells originating in the neural crest. Analysis of the mesenchymal marker vimentin revealed that this protein was markedly down-regulated not only from the epithelial islands, but also from the tumor as a whole, consistent with mesenchymal-to-epithelial transition (MET). In vitro, Prkar1a null primary mouse embryonic fibroblasts, which display constitutive PKA signaling, also showed evidence for MET, with a loss of vimentin and up-regulation of the epithelial marker E-cadherin. Reduction of vimentin protein occurred at the posttranslational level and was rescued by proteasomal inhibition. Finally, this down-regulation of vimentin was recapitulated in the adrenal nodules of CNC patients, confirming an unexpected and previously unrecognized role for PKA in MET.
Nadella
Kiran S
KS
Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA.
Jones
Georgette N
GN
Trimboli
Anthony
A
Stratakis
Constantine A
CA
Leone
Gustavo
G
Kirschner
Lawrence S
LS
D000818:Animals; D002454:Cell Differentiation; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000172:deficiency* / Q000235:genetics*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology* / Q000201:enzymology; D017353:Gene Deletion; D006801:Humans; D008648:Mesoderm / Q000166:cytology* / Q000201:enzymology; D051379:Mice; D018345:Mice, Knockout; D009377:Multiple Endocrine Neoplasia / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D011499:Protein Processing, Post-Translational; D014746:Vimentin / Q000378:metabolism
D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C517834:PRKAR1A protein, human; C517835:Prkar1a protein, mouse; D014746:Vimentin; D017868:Cyclic AMP-Dependent Protein Kinases