Disease relevance of Stat1

• We postulated that lung fibrosis characterized by excessive proliferation of lung fibroblasts would be enhanced in Stat1-deficient (Stat1-/-) mice [1].
• We studied signal transducers and activators of transcription (Stat) expression in mouse trigeminal ganglia (TG) to gain an understanding of herpes simplex virus (HSV) infection and reactivation [2].
• The Stat1S727A mice were more resistant to the LPS-induced septic shock syndrome, suggesting that Stat1 serine phosphorylation promotes inflammatory responses [3].
• Resolution of primary severe acute respiratory syndrome-associated coronavirus infection requires Stat1 [4].
• All four Sendai Virus C proteins bind Stat1, but only the larger forms also induce its mono-ubiquitination and degradation [5].

High impact information on Stat1

• Targeted disruption of the mouse Stat1 gene results in compromised innate immunity to viral disease [6].
• Ligand-induced dimerization of gp130 leads to activation of the Stat1, Stat3 and Shp2-Ras-Erk signaling pathways [7].
• G-CSF receptor was expressed on cardiomyocytes and G-CSF activated the Jak/Stat pathway in cardiomyocytes [8].
• Stat4 was initially cloned as a result of its homology with Stat1 (refs 4, 5) and is widely expressed, although it is only tyrosine-phosphorylated after stimulation of T cells with interleukin (IL)-12 (refs 6,7) [9].
• Actually, Stat1 interacts with Runx2 in its latent form in the cytoplasm, thereby inhibiting the nuclear localization of Runx2, an essential transcription factor for osteoblast differentiation [10].

Biological context of Stat1

• To gain full transcriptional activity, Stat1 also requires serine phosphorylation at S727 [11].
• Stat4 is located on mouse chromosome 1 and is tightly linked to the Stat1 gene, suggesting that the genes arose by gene duplication [12].
• IFNbeta-stimulated apoptosis is the same in pro-B cells derived from wild type and Stat1(-/-) mice [13].
• To determine the signal pathway downstream of Stat1, transcriptional activities of several mutant promoters were examined [14].
• Together, these results demonstrate that SHP-2 is required for the DDR1-induced suppression of Stat1 and Stat3 tyrosine phosphorylation, cell migration, and branching tubulogenesis [15].

Anatomical context of Stat1

• Moreover, IFN-gamma treatment in the absence of growth factors induced a concentration-dependent increase in [3H]thymidine uptake in Stat1-/- but not wild-type fibroblasts [1].
• Stat1 controls postnatal bone formation by regulating fibroblast growth factor signaling in osteoblasts [16].
• IFN-gamma-mediated apoptosis was Stat1-dependent, and was accompanied by loss of mitochondrial membrane potential [17].
• Importantly, Stat1-deficient bone marrow macrophages displayed a similar level of IFN-gamma-stimulated adhesion compared with macrophages derived from wild-type littermates [18].
• A PI-3 kinase-dependent, Stat1-independent signaling pathway regulates interferon-stimulated monocyte adhesion [18].

Associations of Stat1 with chemical compounds

• Jak PTK activation by these IFNs is commonly followed by tyrosine phosphorylation of the transcription factor Stat1 at Y701, which is essential for dimerization, translocation to the nucleus and DNA-binding activity [11].
• Two weeks after bleomycin aspiration (3 U/kg), Stat1-/- mice exhibited a more severe fibroproliferative response and significantly elevated total lung collagen compared to wild-type mice [1].
• These studies show that several Stat, including phosphotyrosine Stat3, are present in TG neurons, the site of HSV latency, where they could act upon latent viral DNA to effect reactivation [2].
• LPS+IFNgamma or hydrogen peroxide activated the Jak2/Stat1/IRF1 pathway and this effect was also inhibited by ascorbate [19].
• A similar deficiency in LPS-induced gene expression was observed in livers and spleens from Stat1-/- mice [20].

Physical interactions of Stat1

• The ability of GH to activate both Stat1 and Stat3 (i.e. increase their tyrosyl phosphorylation and ability to bind to DNA) suggests that gene regulation by GH involves multiple Stat proteins [21].
• Whereas NF-kappaB was constitutively expressed in both cell types, Stat1 phosphorylation and nuclear binding activity were dependent upon IFN-gamma [22].
• In macrophages, this was associated with complete inhibition of NF-kappaB nuclear binding activity and partial (approximately 20-25%) reduction of Stat1 activity [22].
• EMSA analysis using a Stat 5 binding site showed both PRLs to cause equivalent binding of nuclear proteins and that most of what bound was complexed through Stat 5a [23].
• Constitutive activation of Stat-related DNA-binding proteins in erythroid cells by the Friend spleen focus-forming virus [24].

Enzymatic interactions of Stat1

• Stat1 was phosphorylated by IFN-alpha in Tyk2-deficient cells, although the level of phosphorylation was weaker than that observed in wild type mice [25].
• The new function of Stat1 does not require the Tyr 701 that is phosphorylated when Stat1 becomes a transcriptional activator [10].
• When expressed, SOCS-3 binds to phosphorylated Tyr(960) of the insulin receptor and prevents Stat 5B activation by insulin [26].
• Studies are in progress to identify the mechanism by which Stat proteins are phosphorylated in SFFV-infected cells in the absence of Epo [24].
• In fact, the two Stat proteins were tyrosine phosphorylated in IFN-gamma stimulated cells [27].

Regulatory relationships of Stat1

• While IFN-alpha (1000 U/ml) suppressed the number of granulocyte-macrophage colony-forming units (CFU-GM) or erythroid burst-forming units (BFU-E) from wild-type mouse bone marrow cells, this suppression was partially inhibited by a deficiency in Tyk2 and completely inhibited by a deficiency in Stat1 [25].
• Stat 1 and 3 were also activated presumably downstream to JAK2 activation [28].
• In fact, IL-6-induced activation of the Stat1 and Stat3 transcription factors is markedly diminished in the absence of the IFN-alpha/beta signalling complex [29].
• In the case of growth factors whose receptors have intrinsic tyrosine protein kinase activity, it is thought that Stat proteins can be activated either directly by the receptor or indirectly through JAK proteins [30].
• The effect of flagellin on iNOS gene expression was inhibited by a Stat1 mutant protein [31].

Other interactions of Stat1

• Phosphorylation of Stat1 by limitin is partially dependent on Tyk2 [32].
• Therefore, Stat1 and Stat4 independently play substantial roles in the susceptibility to LPS [33].
• Limitin, an interferon-like cytokine, transduces inhibitory signals on B-cell growth through activation of Tyk2, but not Stat1, followed by induction and nuclear translocation of Daxx [32].
• However, at low suboptimal doses of IFN-gamma, Stat1 activation was decreased in TLR2-stimulated cells [34].
• The peptide data also indicate that p77 and p80 are phosphorylated on tyrosine 699, a position analogous to the tyrosine that is phosphorylated in Stat1 and Stat2 in response to interferon [35].

Analytical, diagnostic and therapeutic context of Stat1

• TEL-Jak2 activation resulted in the constitutive tyrosine phosphorylation of Stat1, Stat3, and Stat5 as determined by detection of phosphorylation using activation-specific antibodies and by binding of each protein to a preferential GAS sequence in electrophoretic mobility shift assays [36].
• These findings strongly suggest a link between defects in Stat1 phosphorylation and the failure to up-regulate MHC class I. In all tumour lines tested, the Stat1 Western blotting revealed a 78 kDa protein (p78) not previously described [37].
• Serial 5' deletion and internal deletion of the promoter reveal two important signal transducer and activator of transcription (Stat) binding sites [38].
• Immunoprecipitation of TG nuclear extracts did not confirm the presence of Stat-Stat dimers in these specimens [2].
• In cell culture studies, some of them have been shown to activate members of the family of the signal transducers and activators of transcription (Stat) [39].

References