title: Retinoic acid induces leukemia cell G1 arrest and transition into differentiation by inhibiting cyclin-dependent kinase-activating kinase binding and phosphorylation of PML/RARalpha.
abstract: Acute promyelocytic leukemia (APL) cells express promyelocytic leukemia/retinoic acid receptor alpha (PML/RARalpha) fusion protein, which leads to the blocking of APL cell differentiation. Treatment of APL with all-trans-retinoic acid (ATRA) induces disease remission by in vivo differentiation of APL cells. Differentiation requires cell cycle exit; yet how ATRA couples cell cycle exit to differentiation of APL remains largely unknown. We previously found that ATRA-induced cell differentiation accompanies ubiquitination-proteolysis of ménage à trois 1 (MAT1), an assembly factor and targeting subunit of cyclin-dependent kinase (CDK)-activating kinase (CAK) that regulates G1 exit. We report here that CAK binds to and phosphorylates PML/RARalpha in actively proliferating APL cells. In response to ATRA, PML/RARalpha is dissociated from CAK, leading to MAT1 degradation, G1 arrest, and decreased CAK phosphorylation of PML/RARalpha. CAK phosphorylation of PML/RARalpha is inhibited when MAT1 levels are reduced. Both MAT1 degradation and PML/RARalpha hypophosphorylation occur in ATRA-induced G1-arresting cells undergoing differentiation but not in the synchronized G1 cells that do not differentiate. These findings reveal a novel ATRA signaling on APL cell differentiation, in which ATRA coordinates G1 arrest and transition into differentiation by inducing MAT1 degradation and PML/RARalpha hypophosphorylation through disrupting PML/RARalpha binding and phosphorylation by CAK.
authors.affiliation: Department of Pathology, Childrens Hospital Los Angeles Saban Research Institute, Los Angeles, California 90027, USA.
authors.forename: Jian-guang
authors.initials: JG
authors.lastname: Wang
authors.forename: Lora W
authors.initials: LW
authors.lastname: Barsky
authors.forename: Elai
authors.initials: E
authors.lastname: Davicioni
authors.forename: Kenneth I
authors.initials: KI
authors.lastname: Weinberg
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Triche
authors.forename: Xiao-kun
authors.initials: XK
authors.lastname: Zhang
authors.forename: Lingtao
authors.initials: L
authors.lastname: Wu
mesh_terms: D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects*; D006801:Humans; D007938:Leukemia / Q000473:pathology*; D015514:Oncogene Proteins, Fusion / Q000187:drug effects / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D014157:Transcription Factors; D014212:Tretinoin / Q000494:pharmacology*; D025801:Ubiquitin / Q000378:metabolism; D000095043:Cyclin-Dependent Kinase-Activating Kinase
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C514215:MNAT1 protein, human; D015514:Oncogene Proteins, Fusion; D014157:Transcription Factors; D025801:Ubiquitin; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D014212:Tretinoin; D018844:Cyclin-Dependent Kinases; D010447:Peptide Hydrolases; D000095043:Cyclin-Dependent Kinase-Activating Kinase