title: p38αMAPK interacts with and inhibits RARα: suppression of the kinase enhances the therapeutic activity of retinoids in acute myeloid leukemia cells.
abstract: 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, p38α, 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. P38α inhibits ligand-dependent transactivation of the nuclear retinoic acid receptor, RARα, and the derived chimeric protein expressed in the majority of APL cases, PML-RARα. Inhibition is the consequence of ligand-independent binding of p38α, which results in stabilization of RARα and PML-RARα via blockade of their constitutive degradation by the proteasome. The inhibitory effect requires a catalytically active p38α and direct physical interaction with RARα and PML-RARα. Ser-369 in the E-region of RARα is essential for the binding of p38α and the ensuing functional effects on the activity of the receptor.
authors.affiliation: Laboratory of Molecular Biology, Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Gianni
authors.forename: M
authors.initials: M
authors.lastname: Peviani
authors.forename: N
authors.initials: N
authors.lastname: Bruck
authors.forename: A
authors.initials: A
authors.lastname: Rambaldi
authors.forename: G
authors.initials: G
authors.lastname: Borleri
authors.forename: M
authors.initials: M
authors.lastname: Terao
authors.forename: M
authors.initials: M
authors.lastname: Kurosaki
authors.forename: G
authors.initials: G
authors.lastname: Paroni
authors.forename: C
authors.initials: C
authors.lastname: Rochette-Egly
authors.forename: E
authors.initials: E
authors.lastname: Garattini
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002522:Chlorocebus aethiops; D015973:Gene Expression Regulation, Leukemic; D020868:Gene Silencing; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D011485:Protein Binding; D055550:Protein Stability; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D012176:Retinoids / Q000494:pharmacology* / Q000627:therapeutic use; D014158:Transcription, Genetic
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D015514:Oncogene Proteins, Fusion; C000607071:RARA protein, human; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D012176:Retinoids; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D048308:Mitogen-Activated Protein Kinase 14