IL-6 signaling via the STAT3/SOCS3 pathway: Functional Analysis of the Conserved STAT3 N-domain

Zhang, Ling; Badgwell, Donna; Bevers, Jack; Schlessinger, Karni; Murray, Peter J.; Levy, David E.; Watowich, Stephanie S.

doi:10.1007/s11010-006-9137-3

Cited by 74 publications

(81 citation statements)

References 63 publications

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“…Consequently, inhibition of the ND can affect interactions with other proteins but not phosphorylationdependent STAT3 binding to DNA. A previous report confirmed that STAT3 ND is not essential for P-STAT3 functions in normal fibroblasts (32). Conversely, native gel electrophoresis, dual-focus fluorescence correlation spectroscopy (33), and FRET data suggest that dimerization of unphosphorylated STAT3 requires the ND (34).…”

Section: St3-h2a2mentioning

confidence: 62%

STAT3 suppresses transcription of proapoptotic genes in cancer cells with the involvement of its N-terminal domain

Timofeeva¹,

Tarasova

Zhang³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

124

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Activation of STAT3 in cancers leads to gene expression promoting cell proliferation and resistance to apoptosis, as well as tumor angiogenesis, invasion, and migration. In the characterization of effects of ST3-H2A2, a selective inhibitor of the STAT3 N-terminal domain (ND), we observed that the compound induced apoptotic death in cancer cells associated with robust activation of proapoptotic genes. Using ChIP and tiling human promoter arrays, we found that activation of gene expression in response to ST3-H2A2 is accompanied by altered STAT3 chromatin binding. Using inhibitors of STAT3 phosphorylation and a dominant-negative STAT3 mutant, we found that the unphosphorylated form of STAT3 binds to regulatory regions of proapoptotic genes and prevents their expression in tumor cells but not normal cells. siRNA knockdown confirmed the effects of ST3-HA2A on gene expression and chromatin binding to be STAT3 dependent. The STAT3-binding region of the C/EBP-homologous protein (CHOP) promoter was found to be localized in DNaseI hypersensitive site of chromatin in cancer cells but not in nontransformed cells, suggesting that STAT3 binding and suppressive action can be chromatin structure dependent. These data demonstrate a suppressive role for the STAT3 ND in the regulation of proapoptotic gene expression in cancer cells, providing further support for targeting STAT3 ND for cancer therapy.H3K9me3 | peptide inhibitor | prostate cancer | transcription factor S TAT3, a member of the STAT family, is a key signaling protein that transduces extracellular signals to the nucleus and regulates transcription of genes (1). Following ligand stimulation, STAT3 is phosphorylated on Y705 tyrosine residue, dimerizes, and translocates to the nucleus to bind its cognate DNA-response elements, activating gene transcription (1). Constitutively activated STAT3 mediates deregulated growth, survival, and angiogenesis (2, 3). STAT3 is widely recognized as a potential drug target for cancer therapy, and various approaches, including targeting of upstream tyrosine kinases and direct inhibitors of STAT3 dimerization, have been advanced to inhibit STAT3 signaling in cancers (4). However, unphosphorylated STAT3 (U-STAT3) has also been shown to influence gene transcription, both in response to cytokines and in cancer cells, albeit by mechanisms that are distinct from those activated by phosphorylated STAT3 (5). We have developed a highly selective inhibitor of STAT3 ND, ST3-Hel2A-2 (ST3-H2A2), that binds to the N-terminal domain (ND) and inhibits STAT3 signaling (6). STAT3 ND is involved in the interactions of two STAT dimers on neighboring sites to form a more stable tetramer and the interactions with histone-modifier proteins to induce changes in chromatin structure (reviewed in ref. 7). These complex interactions may greatly affect STAT3-dependent transcriptional activity, suggesting that the STAT3 ND mediates important regulatory functions of STAT3 in normal cells (8) and in cancer (9). ST3-H2A2 induces death in breast cancer cells MDA-MB-231 an...

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Section: St3-h2a2mentioning

confidence: 62%

STAT3 suppresses transcription of proapoptotic genes in cancer cells with the involvement of its N-terminal domain

Timofeeva¹,

Tarasova

Zhang³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

124

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“…29,39 Despite this difference, SOCS3 and IRS-1 changed minimally in C2C12 myotubes treated with rhIL-6 or SAA1 alone. Possibly, mediators other than SAA1 may be required to stimulate muscle protein degradation in vivo.…”

Section: Discussionmentioning

confidence: 97%

“…26 We also evaluated STAT3, an IL-6 -activated transcription factor that stimulates SOCS3 expression. 29 Treatment with rhIL-6 alone led to STAT3 phosphorylation, but the addition of SAA1 and rhIL-6 led to a stronger (P Ͻ 0.05) STAT3 phosphorylation and a major increase in SOCS3 expression. Notably, the increase in p-STAT3 preceded SOCS3 expression ( Figure 7B).…”

Section: Il-6 and Saa Act Synergistically To Increase Socs3 Expressiomentioning

confidence: 88%

IL-6 and Serum Amyloid A Synergy Mediates Angiotensin II–Induced Muscle Wasting

Zhang

et al. 2009

Journal of the American Society of Nephrology

215

244

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Animal studies suggest that increased levels of circulating angiotensin II (AngII) could contribute to the loss of lean body mass in chronic kidney disease, but the mechanism by which this occurs is unclear. Here, AngII infusion increased circulating IL-6 and its hepatic production in wild-type mice, suggesting that AngII-induced inflammation may trigger muscle loss. AngII infusion also stimulated the suppressor of cytokine signaling (SOCS3) in muscle, which led to loss of insulin receptor substrate 1 (IRS-1), thereby impairing insulin/IGF-1 signaling and enhancing protein degradation. All of these responses to AngII were suppressed in IL-6 -deficient mice. Recombinant human IL-6 (rhIL-6) treatment of cultured myotubes only minimally increased SOCS3, however, suggesting the contribution of other mediators. Because AngII increases hepatic serum amyloid A (SAA) expression in an IL-6 -dependent manner, we treated wild-type mice with rhIL-6 and an SAA1-overexpressing adenovirus; the combination led to a significantly greater increase in SOCS3 and decrease in IRS-1 compared with either rhIL-6 or SAA1 alone. We observed similar effects on SOCS3 and IRS-1 when we treated cultured muscle myotubes with rhIL-6 and SAA1. Taken together, these results suggest an interorgan response to high levels of AngII: Hepatic production of IL-6 and SAA increases, and these mediators act synergistically to impair insulin/IGF-1 signaling, which promotes muscle proteolysis. Targeting the high levels of IL-6 and SAA in catabolic disorders might be a therapeutic approach to prevent muscle wasting.

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“…PC1-p30/Src-Dependent Activation of STAT3 Is Insensitive to SOCS3 STAT3 can participate both in a positive and negative feedback mechanism by transcriptionally upregulating its own expression 40 and that of its inhibitor SOCS3, 41 respectively. To test whether PC1-p30/Src-dependent activation of STAT3 can regulate both pathways, we used luciferase reporters driven by the native promotors of the STAT3 and SOCS3 genes, respectively.…”

Section: Regulation Of Src By the Cleaved Pc1 Tailmentioning

confidence: 99%

The Cleaved Cytoplasmic Tail of Polycystin-1 Regulates Src-Dependent STAT3 Activation

Talbot¹,

Song²,

Wang³

et al. 2014

Journal of the American Society of Nephrology

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Polycystin-1 (PC1) mutations result in proliferative renal cyst growth and progression to renal failure in autosomal dominant polycystic kidney disease (ADPKD). The transcription factor STAT3 (signal transducer and activator of transcription 3) was shown to be activated in cyst-lining cells in ADPKD and PKD mouse models and may drive renal cyst growth, but the mechanisms leading to persistent STAT3 activation are unknown. A proteolytic fragment of PC1 corresponding to the cytoplasmic tail, PC1-p30, is overexpressed in ADPKD. Here, we show that PC1-p30 interacts with the nonreceptor tyrosine kinase Src, resulting in Srcdependent activation of STAT3 by tyrosine phosphorylation. The PC1-p30-mediated activation of Src/ STAT3 was independent of JAK family kinases and insensitive to the STAT3 inhibitor suppressor of cytokine signaling 3. Signaling by the EGF receptor (EGFR) or cAMP amplified the activation of Src/STAT3 by PC1-p30. Expression of PC1-p30 changed the cellular response to cAMP signaling. In the absence of PC1-p30, cAMP dampened EGFR-or IL-6-dependent activation of STAT3; in the presence of PC1-p30, cAMP amplified Src-dependent activation of STAT3. In the polycystic kidney (PCK) rat model, activation of STAT3 in renal cystic cells depended on vasopressin receptor 2 (V2R) signaling, which increased cAMP levels. Genetic inhibition of vasopressin expression or treatment with a pharmacologic V2R inhibitor strongly suppressed STAT3 activation and reduced renal cyst growth. These results suggest that PC1, via its cleaved cytoplasmic tail, integrates signaling inputs from EGFR and cAMP, resulting in Src-dependent activation of STAT3 and a proliferative response.

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IL-6 signaling via the STAT3/SOCS3 pathway: Functional Analysis of the Conserved STAT3 N-domain

Cited by 74 publications

References 63 publications

STAT3 suppresses transcription of proapoptotic genes in cancer cells with the involvement of its N-terminal domain

STAT3 suppresses transcription of proapoptotic genes in cancer cells with the involvement of its N-terminal domain

IL-6 and Serum Amyloid A Synergy Mediates Angiotensin II–Induced Muscle Wasting

The Cleaved Cytoplasmic Tail of Polycystin-1 Regulates Src-Dependent STAT3 Activation

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