title: Retinoid-modulated MAT1 ubiquitination and CAK activity.
abstract: Human cyclin-dependent kinase (CDK)-activating kinase (CAK) has a dual function in cross-regulation of cell cycle and differentiation, whereas menage a trois 1 (MAT1) assembles CAK and determines CAK's substrate specificity. Although the dynamic state of MAT1 protein levels is found to modulate CAK activity, how intracellular regulation of MAT1 controls CAK activity is unknown. Recent studies demonstrate that retinoic acid (RA)-induced human HL60 cell proliferation/differentiation (P/D) transition is accompanied by MAT1 degradation and decreased CAK phosphorylation of retinoic acid receptor alpha (RARa). Thus, we investigated the biochemical pathway of MAT1 degradation and its relationship with CAK phosphorylation of RARa. We find that RA induces ubiquitination-proteolysis of MAT1 and that ubiquitin-proteasome targets CAK-free MAT1 only. RA-induced MAT1 ubiquitination reduces CAK abundance and decreases CAK phosphorylation of RARalpha, whereas inhibition of MAT1 ubiquitination resists this RA-effect. These findings reveal that RA induces MAT1 ubiquitination to decrease CAK phosphorylation of RARalpha, suggesting a novel mechanism of RA-mediated P/D transition in which MAT1 ubiquitination may act as an integral part of RA-effect to decrease CAK activity in the switch from proliferation to differentiation.
authors.affiliation: Department of Pathology, University of Southern California Keck School of Medicine, Los Angeles, California 90027, USA.
authors.forename: Qiaojun
authors.initials: Q
authors.lastname: He
authors.forename: Hui
authors.initials: H
authors.lastname: Peng
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Collins
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Triche
authors.forename: Lingtao
authors.initials: L
authors.lastname: Wu
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D018922:HL-60 Cells; D006801:Humans; D010766:Phosphorylation; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin / Q000494:pharmacology*; D014452:Ubiquitins / Q000378:metabolism*; D000095043:Cyclin-Dependent Kinase-Activating Kinase
chemical_list: C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014452:Ubiquitins; D014212:Tretinoin; D018844:Cyclin-Dependent Kinases; D000095043:Cyclin-Dependent Kinase-Activating Kinase