title: Retinoic acid induces signal transducer and activator of transcription (STAT) 1, STAT2, and p48 expression in myeloid leukemia cells and enhances their responsiveness to interferons.
abstract: IFNs are antiproliferative cytokines that have growth-inhibitory effects on various normal and malignant cells. Therefore, they have been used in the treatment of certain forms of cancer, such as chronic myelogenous leukemia and hairy cell leukemia. However, there is little evidence that IFNs would be effective in the treatment of acute myelogenous leukemia, and molecular mechanisms underlying IFN unresponsiveness have not been clarified. Here we have studied the activation and induction of IFN-specific transcription factors signal transducer and activator of transcription (STAT) 1, STAT2, and p48 in all-trans-retinoic acid (ATRA)-differentiated myeloid leukemia cells using promyelocytic NB4, myeloblastic HL-60, and monoblastic U937 cells as model systems. These cells respond to ATRA by growth inhibition and differentiation. We show that in undifferentiated NB4 cells, 2',5'-oligoadenylate synthetase and MxB gene expression is not activated by IFN-alpha, possibly due to a relative lack of signaling molecules, especially p48 protein. However, during ATRA-induced differentiation, steady-state STAT1, STAT2, and especially p48 mRNA and corresponding protein levels were elevated both in NB4 and U937 cells, apparently correlating to an enhanced responsiveness of these cells to IFNs. ATRA treatment of NB4 cells sensitized them to IFN action as seen by increased IFN-gamma activation site DNA-binding activity or by efficient formation of IFN-alpha-specific ISGF3 complex and subsequent oligoadenylate synthetase and MxB gene expression. Lack of p48 expression could be one of the mechanisms of promyelocytic leukemia cell escape from growth-inhibitory effects of IFN-alpha.
authors.affiliation: National Public Health Institute, Helsinki, Finland.
authors.forename: S
authors.initials: S
authors.lastname: Matikainen
authors.forename: T
authors.initials: T
authors.lastname: Ronni
authors.forename: A
authors.initials: A
authors.lastname: Lehtonen
authors.forename: T
authors.initials: T
authors.lastname: Sareneva
authors.forename: K
authors.initials: K
authors.lastname: Melén
authors.forename: S
authors.initials: S
authors.lastname: Nordling
authors.forename: D E
authors.initials: DE
authors.lastname: Levy
authors.forename: I
authors.initials: I
authors.lastname: Julkunen
mesh_terms: D000209:Acute-Phase Proteins / Q000096:biosynthesis / Q000502:physiology; D015152:Blotting, Northern; D015153:Blotting, Western; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology; D019204:GTP-Binding Proteins; D005786:Gene Expression Regulation; D006801:Humans; D050832:Interferon-Stimulated Gene Factor 3; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D016898:Interferon-alpha / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D007951:Leukemia, Myeloid / Q000378:metabolism*; D064547:Myxovirus Resistance Proteins; D009363:Neoplasm Proteins / Q000235:genetics; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000096:biosynthesis* / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects*; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000209:Acute-Phase Proteins; D004268:DNA-Binding Proteins; C494227:IRF9 protein, human; D050832:Interferon-Stimulated Gene Factor 3; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D016898:Interferon-alpha; C579068:MX2 protein, human; D064547:Myxovirus Resistance Proteins; D009363:Neoplasm Proteins; D011506:Proteins; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D014212:Tretinoin; D007371:Interferon-gamma; D019204:GTP-Binding Proteins