title: Delayed tyrosine phosphorylation and nuclear expression of STAT1 following antigen receptor stimulation of B lymphocytes.
abstract: The regulation of the STAT1 alpha transcription factor was assessed during B cell activation induced by cross-linking the surface IgM Ag receptor. Surface Ig ligation or pharmacologic stimulation with PMA and ionomycin resulted in the delayed (2-3 h after stimulation) nuclear appearance of tyrosine-phosphorylated STAT1 alpha, in contrast to the rapid induction that follows cytokine treatment. Nuclear expression of phosphorylated STAT1 alpha was abrogated by co-incubation of anti-Ig-treated B cells with the protein synthesis inhibitor cycloheximide (CHX), with the protein kinase inhibitor H-7, or with the immunosuppressive drug rapamycin. Tyrosine-phosphorylated STAT1 alpha was found to be recruited to the STAT binding site of the IFN regulatory factor-1 (IRF-1) gene promoter only after 2 to 3 h, and this association was also inhibitable by CHX and rapamycin. The arrival of STAT1 alpha coincided with attenuation of anti-Ig-induced STAT-binding activity specific for the IRF-1 promoter site, and both rapamycin and CHX treatment counteracted the loss of this activity. Furthermore, basal transcription of the endogenous IRF-1 gene was decreased as a result of anti-Ig treatment, and this effect of anti-Ig was blocked by co-incubation with rapamycin. Thus, STAT1 alpha plays a dynamic role in the composition of IRF-1 promoter-specific DNA binding complexes stimulated by B cell Ag receptor ligation, and nuclear expression of phosphorylated STAT1 alpha is regulated in a unique fashion by Ag receptor engagement. In addition, surface Ig cross-linking imparts negative regulatory control of IRF-1 gene expression, possibly through activation of STAT1 alpha.
authors.affiliation: Department of Medicine, Boston University Medical Center, MA 02118, USA.
authors.forename: J G
authors.initials: JG
authors.lastname: Karras
authors.forename: L
authors.initials: L
authors.lastname: Huo
authors.forename: Z
authors.initials: Z
authors.lastname: Wang
authors.forename: D A
authors.initials: DA
authors.lastname: Frank
authors.forename: J M
authors.initials: JM
authors.lastname: Zimmet
authors.forename: T L
authors.initials: TL
authors.lastname: Rothstein
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000494:pharmacology; D016475:3T3 Cells; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D015536:Down-Regulation / Q000276:immunology; D050856:Interferon Regulatory Factor-1; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D009698:Nucleoproteins / Q000096:biosynthesis; D010750:Phosphoproteins / Q000096:biosynthesis; D010766:Phosphorylation; D011090:Polyenes / Q000494:pharmacology; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000502:physiology; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*; D050794:STAT1 Transcription Factor; D020123:Sirolimus; D015534:Trans-Activators / Q000096:biosynthesis*; D014157:Transcription Factors / Q000096:biosynthesis; D014443:Tyrosine / Q000378:metabolism*
chemical_list: D000888:Antibodies, Anti-Idiotypic; D004268:DNA-Binding Proteins; D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; D009698:Nucleoproteins; D010750:Phosphoproteins; D011090:Polyenes; D011947:Receptors, Antigen, B-Cell; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D014443:Tyrosine; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D017346:Protein Serine-Threonine Kinases; D020123:Sirolimus