Specificity of signaling by STAT1 depends on SH2 and C-terminal domains that regulate Ser727 phosphorylation, differentially affecting specific target gene expression

Kovarik, Pavel; Mangold, Monika; Ramsauer, Katrin; Heidari, Hamid Reza; Steinborn, Ralf; Zotter, Angelika; Levy, David E.; Müller, Mathias; Decker, Thomas

doi:10.1093/emboj/20.1.91

Cited by 177 publications

(173 citation statements)

References 70 publications

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“…In this context, S727-phosphorylated STAT 1 provided apoptotic resistance for Wilms tumour cells (Timofeeva et al, 2006). Although phosphorylation at Y701 was shown to be sufficient for transactivatory capacity of STAT 1 molecule (Shuai et al, 1993), S727 phosphorylation seems to be an important modulator of target specificity in haemopoetic cells (Kovarik et al, 2001). Perhaps high levels of STAT 1 phosphorylation at S727 might activate specific genes involved in IFN resistance.…”

Section: Relation Between Socss Induction and Stat 1 Phosphorylationmentioning

confidence: 99%

Development of IFN-γ resistance is associated with attenuation of SOCS genes induction and constitutive expression of SOCS 3 in melanoma cells

et al. 2007

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The resistance to interferons (IFNs) limits their anticancer therapeutic efficacy. Here we studied the evolution of an IFN-resistant state in vitro using melanoma cell lines. We found that the cells became less sensitive to antiproliferative effect of IFN-g after prolonged cultivation enabling us to isolate sensitive and resistant subclones of the parental line. We investigated transcription of signal transducer and activator of transcription (STAT) 1 -6 and suppressor of cytokine signalling (SOCS) 1 -3 genes, and phosphorylation of STAT 1 protein. The resistant subline (termed WM 1158R) differed from the sensitive subline (WM 1158S) by a constitutive expression of SOCS 3, lack or weak SOCS 1 -3 activation following IFN-g, and short duration of cytokine activatory signal. Similar correlations were observed in additional melanoma lines differing in IFN sensitivities. At the protein level, IFN-g induced strong and prolonged STAT 1 activation at serine 727 (S727) in WM 1158R while in WM 1158S cells phosphorylation of this amino acid was much less pronounced. On the other hand, phosphorylation of tyrosine 701 (Y701) was stimulated regardless of the sensitivity phenotype. In conclusion, constitutive expression of SOCS 3 is correlated with attenuation of its induction following IFN treatment. These results suggest that progression of melanoma cells from IFN sensitivity to IFN insensitivity associates with changes in SOCS expression.

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Section: Relation Between Socss Induction and Stat 1 Phosphorylationmentioning

confidence: 99%

Development of IFN-γ resistance is associated with attenuation of SOCS genes induction and constitutive expression of SOCS 3 in melanoma cells

et al. 2007

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“…Previous findings indicated that S727 phosphorylated STAT1 acts as an integrator of signals from multiple pathways, resulting in chromatin remodeling and gene activation (Zhang et al, 1998;Ouchi et al, 2000;Kovarik et al, 2001). Therefore, it is conceivable that serine-phosphorylated STAT1 functions as a transcriptional co-activator interacting with other DNA-bound proteins, and its role in cellular processes can be different depending on other proteins expressed and/or activated under the same conditions in cells.…”

Section: Stat1 Is a Prosurvival Factor In Wilms' Tumormentioning

confidence: 99%

Serine-phosphorylated STAT1 is a prosurvival factor in Wilms' tumor pathogenesis

et al. 2006

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Wilms' tumor (WT), one of the most common pediatric solid cancers, arises in the developing kidney as a result of genetic and epigenetic changes that lead to the abnormal proliferation and differentiation of the metanephric blastema. As activation of signal transducers and activators of transcription (STATs) plays an important role in the maintenance/growth and differentiation of the metanephric blastema, and constitutively activated STATs facilitate neoplastic behaviors of a variety of cancers, we hypothesized that dysregulation of STAT signaling may also contribute to WT pathogenesis. Accordingly, we evaluated STAT phosphorylation patterns in tumors and found that STAT1 was constitutively phosphorylated on serine 727 (S727) in 19 of 21 primary WT samples and two WT cell lines. An inactivating mutation of S727 to alanine reduced colony formation of WT cells in soft agar by more than 80% and induced apoptosis under conditions of growth stress. S727-phosphorylated STAT1 provided apoptotic resistance for WT cells via upregulation of expression of the heat-shock protein (HSP)27 and antiapoptotic protein myeloid cell leukemia (MCL)-1. The kinase responsible for STAT1 S727 phosphorylation in WT cells was identified based upon the use of selective inhibitors as protein kinase CK2, not p38, MAP-kinase kinase (MEK)1/2, phosphatidylinositol 3 0 -kinase, protein kinase C or Ca/calmodulindependent protein kinase II (CaMKII). The inhibition of CK2 blocked the anchorage-independent growth of WT cells and induced apoptosis under conditions of growth stress. Our findings suggest that serine-phosphorylated STAT1, as a downstream target of protein kinase CK2, plays a critical role in the pathogenesis of WT and possibly other neoplasms with similar STAT1 phosphorylation patterns.

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“…These studies support the notion that pStat1(ser727) is less critical for IRF-1 expression by stimulation of IFN-γ. However, other studies have reported that IRF-1 expression requires pSTAT1(ser727) (Kovarik et al, 2001;Ramsauer et al, 2002;Varinou et al, 2003). Although the sources of discrepancy between two types of results are not clear at the moment, in all studies, IRF-1 expression was induced by IFN-γ in the absence of serine phosphorylation of Stat1, albeit at a low level.…”

Section: Discussionmentioning

confidence: 76%

Role of PKCδ in IFN-γ-inducible CIITA gene expression☆

Kwon

Yao

Walter

et al. 2007

Molecular Immunology

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The class II transactivator (CIITA) is a key regulatory factor for MHC class II expression. Here, we demonstrate that PKCδ plays an important role in regulating IFN-γ-inducible CIITA gene expression in macrophages. Inhibition of PKCδ by either a PKCδ inhibitor or a dominant negative (DN) mutant form of PKCδ led to down-regulation of CIITA expression. The decrease in CIITA expression by PKCδ inhibition was in part due to the reduced recruitment of serine 727-phosphorylated Stat1 and histone acetyltransferases to the CIITA promoter. As a result, IFN-γ induced histone acetylation at the CIITA promoter is also compromised. However, inhibition of PKCδ did not affect IRF-1 expression or IRF-1 binding to the CIITA promoter. Therefore, we report, for the first time, that PKCδ is an essential signaling molecule to achieve the maximal expression of CIITA in response to IFN-γ in macrophages. In addition, although IRF-1 is a key transcription factor to activate the IFN-γ inducible CIITA promoter, the effect of PKCδ on CIITA expression is mediated primarily by serine phosphorylation of Stat1.

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Specificity of signaling by STAT1 depends on SH2 and C-terminal domains that regulate Ser727 phosphorylation, differentially affecting specific target gene expression

Cited by 177 publications

References 70 publications

Development of IFN-γ resistance is associated with attenuation of SOCS genes induction and constitutive expression of SOCS 3 in melanoma cells

Development of IFN-γ resistance is associated with attenuation of SOCS genes induction and constitutive expression of SOCS 3 in melanoma cells

Serine-phosphorylated STAT1 is a prosurvival factor in Wilms' tumor pathogenesis

Role of PKCδ in IFN-γ-inducible CIITA gene expression☆

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