title: Opposing effects of PML and PML/RAR alpha on STAT3 activity.
abstract: Promyelocytic leukemia protein PML acts as a tumor suppressor, whereas its chimeric mutant promyelocytic leukemia/retinoic acid receptor alpha (PML/RAR alpha) causes acute promyelocytic leukemia (APL). Because PML has been shown to form transcription-regulatory complexes with various molecules, we speculated that PML and/or PML/RAR alpha might affect signal transducer and activator of transcription 3 (STAT3) activity, which plays a crucial role in granulocyte colony-stimulating factor (G-CSF)-induced growth and survival of myeloid cells. In luciferase assays, PML inhibited STAT3 activity in NIH3T3, 293T, HepG2, and 32D cells. PML formed a complex with STAT3 through B-box and COOH terminal regions in vitro and in vivo, thereby inhibiting its DNA binding activity. Although PML/RAR alpha did not interact with STAT3, it dissociated PML from STAT3 and restored its activity suppressed by PML. To assess the biologic significance of these findings, we introduced PML and PML/RAR alpha into interleukin-3 (IL-3)-dependent Ba/F3 cells expressing the chimeric receptor composed of extracellular domain of G-CSF-R and cytoplasmic domain of gp130, in which gp130-mediated growth is essentially dependent on STAT3 activity. Neither PML nor PML/RAR alpha affected IL-3-dependent growth of these clones. By contrast, gp130-mediated growth was abrogated by PML, whereas it was enhanced by PML/RAR alpha. These results reveal new functions of PML and PML/RAR alpha and suggest that dysregulated STAT3 activity by PML/RAR alpha may participate in the pathogenesis of APL.
authors.affiliation: Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Kawasaki
authors.forename: Itaru
authors.initials: I
authors.lastname: Matsumura
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Kataoka
authors.forename: Eri
authors.initials: E
authors.lastname: Takigawa
authors.forename: Koichi
authors.initials: K
authors.lastname: Nakajima
authors.forename: Yuzuru
authors.initials: Y
authors.lastname: Kanakura
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001667:Binding, Competitive; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D002460:Cell Line / Q000187:drug effects; D018076:DNA, Complementary / Q000235:genetics; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D024202:Electrophoretic Mobility Shift Assay; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000196:embryology; D015473:Leukemia, Promyelocytic, Acute / Q000209:etiology* / Q000378:metabolism; D008113:Liver Neoplasms / Q000473:pathology; D046911:Macromolecular Substances; D051379:Mice; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000494:pharmacology* / Q000502:physiology; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion / Q000494:pharmacology*; D000071156:Promyelocytic Leukemia Protein; D011485:Protein Binding; D025941:Protein Interaction Mapping; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000502:physiology; D014157:Transcription Factors / Q000494:pharmacology*; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects; D025521:Tumor Suppressor Proteins
chemical_list: D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D046911:Macromolecular Substances; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; D011993:Recombinant Fusion Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; C070576:PML protein, human