title: A function of p21 during promyelocytic leukemia cell differentiation independent of CDK inhibition and cell cycle arrest.
abstract: Retinoic Acid (RA) treatment induces disease remission of Acute Promyelocytic Leukemias (APL) by triggering differentiation of neoplastic cells. Differentiation is mediated by the APL-specific transforming protein PML/RAR alpha and involves its activity as ligand-dependent enhancer factor on RA-target genes. We report here the identification of p21 as a transcriptional target of PML/RAR alpha during RA-induced differentiation of APL cells. We found that RA-treated APL cells undergo two rounds of cell division before entering post mitotic G1, that progression through the G1-S is indispensable for differentiation and coincides with the duration of commitment. RA-treatment induced two peaks of p21 synthesis: early (from the 2nd to the 6th hour), dependent on PML/RAR alpha expression and associated with G1-S transition and high CDK activity; late (from 3rd to the 4th day), independent from PML/RAR alpha and associated with G1 block and low CDK activity. Increased p21 in PML/RAR alpha cells during G1-S had no effect on the cell cycle while an antisense p21 prevented RA-induced differentiation without altering G1-S transition and the late G1 block. These results demonstrate that p21 is an effector of the activity of PML/RAR alpha on differentiation and suggest that p21 exerts a function in G1-S connected to differentiation-commitment and uncoupled from cell cycle and CDK inhibition.
authors.affiliation: European Institute of Oncology, Department of Experimental Oncology, Milan, Italy.
authors.forename: T
authors.initials: T
authors.lastname: Casini
authors.forename: P G
authors.initials: PG
authors.lastname: Pelicci
mesh_terms: D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle; D002454:Cell Differentiation; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D016213:Cyclins / Q000096:biosynthesis* / Q000235:genetics; D016193:G1 Phase; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000503:physiopathology*; D009363:Neoplasm Proteins / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D016196:S Phase; D014212:Tretinoin / Q000378:metabolism / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D020298:U937 Cells; D015854:Up-Regulation
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D014212:Tretinoin; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases