p38alphaMAPK interacts with and inhibits RARalpha: suppression of the kinase enhances the therapeutic activity of retinoids in acute myeloid leukemia cells.
Fiche publication
Date publication
août 2012
Auteurs
Membres identifiés du Cancéropôle Est :
Dr ROCHETTE-EGLY Cécile
Tous les auteurs :
Gianni M, Peviani M, Bruck N, Rambaldi A, Borleri G, Terao M, Kurosaki M, Paroni G, Rochette-Egly C, Garattini E
Lien Pubmed
Résumé
All-trans retinoic acid (ATRA) is the only clinically useful differentiating agent, being used in the treatment of acute promyelocytic leukemia (APL). The use of ATRA in other types of acute myelogenous leukemia (AML) calls for the identification of novel strategies aimed at increasing its therapeutic activity. Here, we provide evidence that pharmacological inhibition of the mitogen-activated protein kinase, p38alpha, or silencing of the corresponding gene sensitizes APL and AML cell lines, as well as primary cultures of AML blasts to the anti-proliferative and cyto-differentiating activity of ATRA and synthetic retinoids. P38alpha inhibits ligand-dependent transactivation of the nuclear retinoic acid receptor, RARalpha, and the derived chimeric protein expressed in the majority of APL cases, PML-RARalpha. Inhibition is the consequence of ligand-independent binding of p38alpha, which results in stabilization of RARalpha and PML-RARalpha via blockade of their constitutive degradation by the proteasome. The inhibitory effect requires a catalytically active p38alpha and direct physical interaction with RARalpha and PML-RARalpha. Ser-369 in the E-region of RARalpha is essential for the binding of p38alpha and the ensuing functional effects on the activity of the receptor.
Référence
Leukemia. 2012 Aug;26(8):1850-61