title: Importance of serine727 phosphorylated STAT1 in IFNγ-induced signaling and apoptosis of human salivary gland cells.
abstract: OBJECTIVE
  It is reported that in salivary glands of Sjögren's syndrome (SS), interferon gamma (IFNγ) and IFNγ-inducible genes containing signal transducers and activators of transcription 1 (STAT1) are upregulated and play a crucial role in the pathogenesis of SS. The aim of this study is to clarify which phosphorylation of STAT1, serine727 (Ser(727)) or tyrosine701 (Tyr(701)) of STAT1, is important for IFNγ signaling and IFNγ-induced apoptosis in salivary gland cells.
  
  
  METHODS
  We established STAT1 Tyr(701) variant (tyrosine to phenylalanine; Y701F) and STAT1 Ser(727) variant (serine to alanine; S727A), which were transfected into human salivary gland (HSG) cells. HSG cells transfected with these mutant-STAT1 were analyzed on the expression of IFNγ-inducible genes and apoptosis after stimulation with IFNγ.
  
  
  RESULTS
  In Y701F mutant-STAT1 transfected HSG cells (Ser(727)-dominant HSG cells), IFNγ-inducible genes such as IP10, IRF1, and Fas expression were increased after stimulation with IFNγ. In Ser(727)-dominant HSG cells, the induction of apoptosis after stimulation with IFNγ was also increased compared with S727A mutant-STAT1 transfected HSG cells (Tyr(701)-dominant HSG cells).
  
  
  CONCLUSIONS
  Phosphorylation of Ser(727) in STAT1 might be more important in IFNγ signaling and the induction of apoptosis in HSG cells than phosphorylation of Tyr(701). Accordingly, we propose that phosphorylation of Ser(727) in STAT1 could be a potentially suitable new therapeutic target for SS patients to prevent the destruction of salivary glands.
authors.affiliation: Division of Clinical Immunology, Doctoral Programs in Clinical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Tsuboi
authors.forename: Ei
authors.initials: E
authors.lastname: Wakamatsu
authors.forename: Mana
authors.initials: M
authors.lastname: Iizuka
authors.forename: Yumi
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Makoto
authors.initials: M
authors.lastname: Sugihara
authors.forename: Takeshi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ogishima
authors.forename: Taichi
authors.initials: T
authors.lastname: Hayashi
authors.forename: Daisuke
authors.initials: D
authors.lastname: Goto
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ito
authors.forename: Isao
authors.initials: I
authors.lastname: Matsumoto
authors.forename: Takayuki
authors.initials: T
authors.lastname: Sumida
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D009154:Mutation; D010766:Phosphorylation; D050794:STAT1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D012469:Salivary Glands / Q000187:drug effects* / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D012859:Sjogren's Syndrome / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism
chemical_list: D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D014443:Tyrosine; D012694:Serine; D007371:Interferon-gamma