title: Retinoic acid-induced cell cycle arrest of human myeloid cell lines is associated with sequential down-regulation of c-Myc and cyclin E and posttranscriptional up-regulation of p27(Kip1).
abstract: All-trans retinoic acid (ATRA) is a potential therapeutic agent for the treatment of hematopoietic malignancies, because of its function as an inducer of terminal differentiation of leukemic blasts. Although the efficacy of ATRA as an anticancer drug has been demonstrated by the successful treatment of acute promyelocytic leukemia (APL), the molecular mechanisms of ATRA-induced cell cycle arrest of myeloid cells have not been fully investigated. In this study, we show that the onset of ATRA-induced G(0)/G(1) arrest of human monoblastic U-937 cells is linked to a sharp down-regulation of c-Myc and cyclin E levels and an increase in p21(WAF1/CIP1) expression. This is followed by an increase in p27(Kip1) protein expression due to enhanced protein stability. The importance of an early decrease in Myc expression for these events was demonstrated by the failure of a U-937 subline with constitutive exogenous expression of v-Myc to cell cycle arrest and regulate cyclin E and p27(Kip1) in response to ATRA. Preceding the initiation of G(1) arrest, a transient rise in retinoblastoma protein (pRb), p107, and cyclin A levels was detected. Later, a rapid fall in the levels of cyclins A and B and a coordinate dephosphorylation of pRb at Ser780, Ser795, and Ser807/811 coincided with the accumulation of cells in G(1). These results thus identify a decrease in c-Myc and cyclin E levels and a posttranscriptional up-regulation of p27(Kip1) as important early changes, and position them in the complex chain of events regulating ATRA-induced cell cycle arrest of myeloid cells.
authors.affiliation: Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, S-751 85 Uppsala, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Dimberg
authors.forename: Fuad
authors.initials: F
authors.lastname: Bahram
authors.forename: Inger
authors.initials: I
authors.lastname: Karlberg
authors.forename: Lars-Gunnar
authors.initials: LG
authors.lastname: Larsson
authors.forename: Kenneth
authors.initials: K
authors.lastname: Nilsson
authors.forename: Fredrik
authors.initials: F
authors.lastname: Oberg
mesh_terms: D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D007399:Interphase / Q000187:drug effects; D007700:Kinetics; D022423:Myeloid Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology* / Q000502:physiology; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016271:Proto-Oncogene Proteins c-myc; D016160:Retinoblastoma Protein; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D014212:Tretinoin