Identification of a High-Affinity Phosphopeptide Inhibitor of Stat3

Ren, Zhiyong; Cabell, Larry A.; Schaefer, Timothy S.; McMurray, John S.

doi:10.1016/s0960-894x(02)01050-8

Cited by 121 publications

(120 citation statements)

References 23 publications

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“…Although these agents predominantly block Jak͞Stat activity, they can affect other signaling pathways. Recently, more specific Stat3 peptide inhibitors have been developed by fusing the Stat3 SH2 binding domain to a membrane-translocating sequence, which allows delivery of the active peptide to cells in vitro (22,30,31). The peptide used in this study contains the Stat3 SH2 domain binding peptide PYLKTK, where Y represents phosphotyrosine.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Stat3 activation in the endometrium prevents implantation: A nonsteroidal approach to contraception

Catalano

Johnson

Campbell

et al. 2005

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

107

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Activation of the receptors for leukemia inhibitory factor (LIF) and IL-11 is essential for embryo attachment and decidualization in mice. Both receptors induce activation of the Stat family of signal transducers via the Jak͞Stat pathway. Here, we aimed to establish whether activation of Stat3 in maternal endometrium is essential for successful implantation. Functional blockade of Stat3 before implantation, by injection into the uterine lumen of a cell-permeable Stat3 peptide inhibitor, reduced embryo implantation specifically by 70% (P < 0.001). 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. The inhibitor also blocked induction by LIF of several LIF-regulated genes in the LE including Irg1, which has been shown previously to be essential for implantation. Successful implantation is therefore dependent on phosphorylation and activation of Stat3 in the endometrium before implantation. This finding provides a target for contraceptive development, based on selective blockade of signal transduction pathways essential for implantation. This study demonstrates that cell-permeable peptide inhibitors can be used effectively to target intracellular signaling pathways in the uterine LE.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Stat3 activation in the endometrium prevents implantation: A nonsteroidal approach to contraception

Catalano

Johnson

Campbell

et al. 2005

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

107

View full text Add to dashboard Cite

show abstract

“…Several strategies have been pursued for developing inhibitors of Stat3, based on the complex nature of its gene expression and activity. Strategies to abolish Stat3 expression include the delivery of antisense oligonucleotides and small interfering RNA, whereas approaches for inhibition of Stat3 activity include the use of tyrosine kinase inhibitors, phosphopeptides, G-quartet oligodeoxynucleotides, decoy oligonucleotides, and small-molecule compounds that inhibit DNA-binding (39)(40)(41)(42)(43)(44)(45)(46)(47). Among these strategies against Stat3 is the use of smallmolecule inhibitors, such as JSI-124, WP1066, STA-21, and IS3 295, which have the most immediate therapeutic potential.…”

Section: Clinical-translational Advancesmentioning

confidence: 99%

Regulation of Metastases by Signal Transducer and Activator of Transcription 3 Signaling Pathway: Clinical Implications

Huang

2007

Clinical Cancer Research

222

185

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Numerous cytokines, growth factors, and oncogenic proteins activate signal transducer and activator of transcription 3 (Stat3), which has been recognized as one of the common pathways in cancer cells. Stat3 signaling affects the expression and function of a variety of genes that are critical to cell survival, cell proliferation, invasion, angiogenesis, and immune evasion. Evidently, the Stat3 signaling pathway regulates cancer metastasis and constitutes a potential preventive and therapeutic target for cancer metastasis.

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“…Oncogenic tyrosine kinases such as v-Src can phosphorylate and activate STAT3 in a cytokine-independent manner and thereby contribute to tumor formation (16,17). STAT3 inhibitors are under development for the treatment of certain cancers including those of the head, neck and prostate (18)(19)(20). Furthermore, the STAT3 pathway may provide a therapeutic target for certain immune-mediated disorders including rheumatoid arthritis (1,10,12,21).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2006

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The conserved N-domain of the STAT proteins has been implicated in several activities crucial to cytokine signaling including receptor recruitment and STAT activation, cooperative DNA binding and STAT-dependent gene expression. We evaluated the role of the STAT3 N-domain in the IL-6 signal transduction pathway leading to Socs3 gene expression, an essential mechanism that controls the quality and magnitude of IL-6-dependent transcriptional responses. Based on the model for STAT N-domain function in cooperative gene expression and the presence of tandem STAT binding motifs in the murine Socs3 promoter, we anticipated that stabilizing interactions between adjacent STAT3 dimers via N-domain sequences might be essential for Socs3 gene expression. This was underscored by the tight conservation in the location and sequence of the tandem STAT binding sites between the murine and human Socs3 promoters. Using reconstitution into Stat3−/− mouse embryonic fibroblasts (Stat3−/− MEFs), we find that a STAT3 N-domain deletion mutant (Δ133STAT3) is activated by tyrosine phosphorylation in response to IL-6 and then undergoes dephosphorylation with kinetics similar to full-length STAT3. These results highlight important differences compared to other STATs where the N-domain has been shown to mediate activation (STAT4) or dephosphorylation (STAT1). STAT3 binds predominantly to a single STAT consensus site in the Socs3 promoter, despite the presence of an adjacent STAT motif. Significantly, Δ133STAT3 stimulates expression of the endogenous Socs3 gene in Stat3−/− MEFs upon IL-6 treatment with an activity similar to reconstituted STAT3, demonstrating that the N-domain is dispensable for Socs3 gene expression. We propose that the Socs3 gene in its chromosomal context is activated by the IL-6/ STAT3 pathway independent of STAT3 N-domain sequences.

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Identification of a High-Affinity Phosphopeptide Inhibitor of Stat3

Cited by 121 publications

References 23 publications

Inhibition of Stat3 activation in the endometrium prevents implantation: A nonsteroidal approach to contraception

Inhibition of Stat3 activation in the endometrium prevents implantation: A nonsteroidal approach to contraception

Regulation of Metastases by Signal Transducer and Activator of Transcription 3 Signaling Pathway: Clinical Implications

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

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