title: Phosphorylation-deficient Stat1 inhibits retinoic acid-induced differentiation and cell cycle arrest in U-937 monoblasts.
abstract: All-trans retinoic acid (ATRA) is a potent inducer of terminal differentiation of immature leukemic cell lines in vitro and of acute promyelocytic leukemia (APL) cells in vivo. Recent reports have shown that ATRA induces the expression of several interferon-regulated genes, including signal transducer and activator of transcription (Stat)1. To investigate the role of Stat1 activation in ATRA signaling, sublines were established for the human monoblastic cell line U-937 constitutively expressing wild-type or phosphorylation-defective Stat1, mutated in the conserved tyrosine 701 required for dimerization and nuclear translocation. Results showed that ATRA induction leads to activation of Stat1 by the phosphorylation of tyrosine 701 and subsequent nuclear translocation. Consistent with a functional importance of this activation, ectopic expression of Stat1(Y701F) suppressed ATRA-induced morphologic differentiation and expression of the monocytic surface markers CD11c and the granulocyte colony-stimulating factor receptor. Moreover, ATRA-induced growth arrest in the G(0)/G(1) phase of the cell cycle was inhibited by phosphorylation-deficient Stat1. Taken together, these results indicate that Stat1 is a key mediator of ATRA-induced cell cycle arrest and differentiation of U-937 cells. (Blood. 2000;96:2870-2878)
authors.affiliation: Department of Genetics and Pathology, Section of Pathology, The Rudbeck Laboratory, Uppsala University, SE-75185, Uppsala, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Dimberg
authors.forename: K
authors.initials: K
authors.lastname: Nilsson
authors.forename: F
authors.initials: F
authors.lastname: Oberg
mesh_terms: D019943:Amino Acid Substitution; D001692:Biological Transport / Q000235:genetics; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D002762:Cholecalciferol / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D016193:G1 Phase; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005799:Genes, Dominant; D017930:Genes, Reporter; D006801:Humans; D050856:Interferon Regulatory Factor-1; D016297:Mutagenesis, Site-Directed; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000502:physiology; D011499:Protein Processing, Post-Translational; D011993:Recombinant Fusion Proteins / Q000502:physiology; D016192:Resting Phase, Cell Cycle; D050794:STAT1 Transcription Factor; D015534:Trans-Activators / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects*; D014162:Transfection; D014212:Tretinoin / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D020298:U937 Cells / Q000166:cytology / Q000187:drug effects*
chemical_list: D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D009363:Neoplasm Proteins; D010750:Phosphoproteins; D011993:Recombinant Fusion Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D002762:Cholecalciferol; D019000:Phosphotyrosine; D014212:Tretinoin