title: cAMP-Dependent Protein Kinase A (PKA)-Mediated c-Myc Degradation Is Dependent on the Relative Proportion of PKA-I and PKA-II Isozymes.
abstract: The transcription factor c-Myc regulates numerous target genes that are important for multiple cellular processes such as cell growth and differentiation. It is commonly deregulated in leukemia. Acute promyelocytic leukemia (APL) is characterized by a blockade of granulocytic differentiation at the promyelocyte stage. Despite the great success of all-trans retinoic acid (ATRA)-based therapy, which results in a clinical remission by inducing promyelocyte maturation, a significant number of patients relapse due to the development of ATRA resistance. A significant role has been ascribed to the cAMP/cAMP-dependent protein kinase A (PKA) signaling pathway in retinoid treatment since PKA activation is able to restore differentiation in some ATRA-resistant cells and eradicate leukemia-initiating cells in vivo. In this study, using NB4 APL cell variants resistant to ATRA-induced differentiation, we reveal distinct functional roles of the two PKA isozymes, PKA type I (PKA-I) and PKA-type II (PKA-II), on the steady-state level of c-Myc protein, providing a likely mechanism by which cAMP-elevating agents can restore differentiation in ATRA maturation-resistant APL cells. Therefore, both the inhibition of c-Myc activity and the PKA-I/PKA-II ratio should be taken into account if cAMP-based therapy is considered in the clinical management of APL.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale UMR-S 1007, Homéostasie Cellulaire et Cancer, Université Paris-Descartes, Paris Sorbonne Cité, Paris, France (Q.L., E.N., E.S.-B.); and Department of Biomedicine, University of Bergen, Bergen, Norway (S.D.).
authors.forename: Qingyuan
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Institut National de la Santé et de la Recherche Médicale UMR-S 1007, Homéostasie Cellulaire et Cancer, Université Paris-Descartes, Paris Sorbonne Cité, Paris, France (Q.L., E.N., E.S.-B.); and Department of Biomedicine, University of Bergen, Bergen, Norway (S.D.).
authors.forename: Eric
authors.initials: E
authors.lastname: Nguyen
authors.affiliation: Institut National de la Santé et de la Recherche Médicale UMR-S 1007, Homéostasie Cellulaire et Cancer, Université Paris-Descartes, Paris Sorbonne Cité, Paris, France (Q.L., E.N., E.S.-B.); and Department of Biomedicine, University of Bergen, Bergen, Norway (S.D.).
authors.forename: Stein
authors.initials: S
authors.lastname: Døskeland
authors.affiliation: Institut National de la Santé et de la Recherche Médicale UMR-S 1007, Homéostasie Cellulaire et Cancer, Université Paris-Descartes, Paris Sorbonne Cité, Paris, France (Q.L., E.N., E.S.-B.); and Department of Biomedicine, University of Bergen, Bergen, Norway (S.D.) evelyne.segal-bendirdjian@inserm.fr.
authors.forename: Évelyne
authors.initials: É
authors.lastname: Ségal-Bendirdjian
mesh_terms: D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism; D055550:Protein Stability; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*
chemical_list: D007527:Isoenzymes; D016271:Proto-Oncogene Proteins c-myc; D017868:Cyclic AMP-Dependent Protein Kinases