RT Journal Article
SR Electronic
T1 cAMP Dependent Protein Kinase (PKA)-Mediated c-Myc Degradation is Dependent on the Relative Proportion of PKA-I and PKA-II Isozymes
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.115.097915
DO 10.1124/mol.115.097915
A1 Qingyuan LIU
A1 Eric NGUYEN
A1 Stein DOSKELAND
A1 Evelyne SEGAL-BENDIRDJIAN
YR 2015
UL http://molpharm.aspetjournals.org/content/early/2015/06/23/mol.115.097915.abstract
AB 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 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-PKA signaling pathway in retinoid treatment since PKA activation is able to restore differentiation in some ATRA-resistant cells and also 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-I and 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.