Disease relevance of Stat3

• However, estrogen-induced decrease in body weight was dependent on Stat3 activation in the brain [1].
• In this study, we analyzed the mechanism by which a Stat3 deficiency in myeloid cells led to the induction of chronic enterocolitis in vivo [2].
• Finally, we addressed the effect of targeting Stat3 in in vivo growth of C4HD breast tumors [3].
• In the present study, we explored the capacity of progestins to modulate Stat3 transcriptional activation in an experimental model of hormonal carcinogenesis in which the synthetic progestin medroxyprogesterone acetate (MPA) induced mammary adenocarcinomas in BALB/c mice and in the human breast cancer cell line T47D [3].
• Both Y704 and Y744 contributed to optimal activation of Stat3/beta in M1 murine myeloid leukemia cells containing wild-type and Y-to-F mutant G-CSFR constructs [4].
• The coexpressed Stat3-specific shRNA and GRIM-19 synergistically and more effectively suppressed prostate tumor growth and metastases when compared with treatment with either single agent alone [5].

High impact information on Stat3

• In this issue of Cell, and add a new transcriptional operating system to the known Oct4 and Stat3 systems required for early embryonal stem cell potency and self-renewal [6].
• Despite intact expression and phosphorylation of Stat3alpha, overall Stat3 activity was impaired in Stat3beta(-/-) cells [7].
• Alternative splicing of the gene for Stat3, a transcription factor activated by the IL-6 family of cytokines, produces two isoforms: Stat3alpha and a dominant-negative variant, Stat3beta [7].
• Specific ablation of Stat3beta distorts the pattern of Stat3-responsive gene expression and impairs recovery from endotoxic shock [7].
• In many human cancers and transformed cell lines, Stat3 is persistently activated, and in cell culture, active Stat3 is either required for transformation, enhances transformation, or blocks apoptosis [8].

Psychiatry related information on Stat3

• These data demonstrate that Stat3-dependent signaling in AgRP neurons in the ARC controls locomotor activity independently of AgRP regulation [9].

Chemical compound and disease context of Stat3

• Our results have for the first time demonstrated that progestins are able to induce Stat3 transcriptional activation, which is in turn an obligatory requirement for progestin stimulation of both in vitro and in vivo breast cancer growth [3].
• Our findings, taken together, suggest that tyrosine kinases transduce signals through Stat3 protein that contribute to the growth and survival of human breast cancer cells in culture and potentially in vivo [10].
• Furthermore, blockade of activated Stat3 in highly metastatic C4 cells significantly suppressed the invasiveness of the tumor cells, inhibited tumor growth, and prevented metastasis in nude mice [11].
• RESULTS: We show that the levels of activated Stat3 are associated with the progression of androgen-independent prostate cancer [12].
• However, these mice did not develop glucose intolerance or obesity over a period of 6 months, demonstrating that Stat3 is dispensable for the generation and physiology of beta-cells [13].

Biological context of Stat3

• Specific inhibition of Stat3 signal transduction by PIAS3 [14].
• PIAS3 blocked the DNA-binding activity of Stat3 and inhibited Stat3-mediated gene activation [14].
• To address the function of this signaling molecule in mammary epithelial apoptosis, we have generated a conditional knockout of Stat3 using the Cre-lox recombination system [15].
• Our findings suggest that IGFBP-5 is a direct or indirect target for Stat3 and its upregulation is essential to normal involution [15].
• Stat3 may be a key molecule which determines the cellular decision from cell growth to differentiation in M1 cells [16].

Anatomical context of Stat3

• Suppression of epithelial apoptosis and delayed mammary gland involution in mice with a conditional knockout of Stat3 [15].
• Furthermore, enterocolitis was significantly improved and IFN-gamma production by T cells was reduced in TLR4/Stat3 double-mutant mice, indicating that TLR4-mediated recognition of microbial components triggers aberrant IL-12p40 production by myeloid cells, leading to the development of enterocolitis [2].
• We show here that disruption of Stat3 signaling by using dominant-negative Stat3beta protein in NIH 3T3 fibroblasts suppresses c-Myc expression concomitant with inhibition of v-Src-induced transformation [17].
• In normal NIH 3T3 cells, disruption of Stat3 signaling with dominant-negative Stat3beta protein inhibits PDGF-induced mitogenesis in a manner that is reversed by ectopic c-Myc expression [17].
• We found that C4HD epithelial cells, from the MPA-induced mammary tumor model, expressed Stat3 and that MPA treatment of C4HD cells up-regulated Stat3 protein expression [3].

Associations of Stat3 with chemical compounds

• Anorectic estrogen mimics leptin's effect on the rewiring of melanocortin cells and Stat3 signaling in obese animals [1].
• The studies reported here were undertaken to determine which, if any, of these tyrosine residues participated in Stat3/beta recruitment and activation [4].
• Treatment of C4HD cells with MPA induced Stat3 binding to DNA [3].
• Y744 is followed at the +3 position by Cys (C); YXXC, represents a novel motif implicated in the recruitment and activation of Stat3 [4].
• To identify small molecule inhibitors of Stat3, we investigated the ability of the Stat3 SH2 domain-binding peptide, PY*LKTK (where Y* represents phosphotyrosine), to disrupt Stat3 activity in vitro [18].

Physical interactions of Stat3

• 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 [19].
• BATF forms complexes with c-Jun in M1 cells and forced expression of BATF in the absence of Stat3 signaling results in a reduced rate of cellular growth [20].
• Chromatin immunoprecipitation assays show that Stat3 binds directly to the p55alpha and p50alpha promoters in vivo [21].
• Utilising a dominant negative mutant of p21ras we demonstrate that both insulin-induced Stat3 DNA-binding and also transactivation do not require p21ras [22].

Enzymatic interactions of Stat3

• We conclude that Stat3 isoforms can be directly phosphorylated and thereby activated in vitro by the epidermal growth factor receptor kinase [23].
• Stat3 is phosphorylated in the luminal epithelium (LE) in response to LIF, and this phosphorylation was significantly reduced both in vitro and in vivo by the Stat3 inhibitor [24].
• Immunoblot experiments showed that tyrosine phosphorylation of Stat3 increased in total cellular extracts and that the phosphorylated protein translocated into the nucleus upon leptin treatment [25].
• We find that Stat3 is tyrosine-phosphorylated and present in mouse liver nuclei following either EGF or lipopolysaccharide administration [26].

Regulatory relationships of Stat3

• Moreover, we demonstrated that injection of IL-6 into virgin and lactating mice activates Stat3 in mammary epithelium [27].
• Hypothalami from these mice also display markedly increased leptin-induced Stat3 phosphorylation [28].
• In conclusion, LIF-induced mast cell growth in the co-culture system is mediated by an indirect pathway via 3T3 fibroblasts through activating Stat3 signaling pathway in 3T3 fibroblasts [29].
• The latent transcription factor Stat3 is activated by gp130, the common receptor for the interleukin (IL)-6 cytokine family and other growth factor and cytokine receptors [30].
• Treatment of cultured C2C12 myotubes with ephrin-A1 also induced tyrosine phosphorylation of Stat3, which was abolished by the Jak2 inhibitor AG490 [31].

Other interactions of Stat3

• Even in the absence of Stat1, which is essential for IFN-gamma signaling pathways, Stat3 mutant mice developed chronic enterocolitis [2].
• Ectopic expression of c-Myc is able to partially reverse this inhibition, suggesting that c-Myc is a downstream effector of Stat3 signaling in v-Src transformation [17].
• Here we report a novel signaling pathway of EphA4, which involves activation of the tyrosine kinase Jak2 and the transcriptional activator Stat3 [31].
• Activation of Tyk2 and Stat3 is required for the apoptotic actions of interferon-beta in primary pro-B cells [32].
• However, Stat3 activation during involution was independent of the IL-6 status [27].

Analytical, diagnostic and therapeutic context of Stat3

• Progestins induce transcriptional activation of signal transducer and activator of transcription 3 (Stat3) via a Jak- and Src-dependent mechanism in breast cancer cells [3].
• 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 [33].
• Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway [34].
• Immunoprecipitation analyses using lysates from TPA-treated epidermis and skin papillomas showed enhanced interaction between the EGFR and Stat3 [35].
• Stat1, Stat3, and Stat5 were activated in mouse epidermis after treatment with different classes of tumor promoters, including 12-O-tetradecanoylphorbol-13-acetate (TPA), okadaic acid, and chrysarobin [35].

References