Jak-STAT Pathways and Transcriptional Activation in Response to IFNs and Other Extracellular Signaling Proteins

Darnell, James; Kerr, Ian M.; Stark, George Stark

doi:10.1126/science.8197455

Cited by 5,511 publications

(3,915 citation statements)

References 69 publications

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“…Levels of STAT3 bound to the miR‐7 promoter probe, observed in E2‐treated young fibroblasts, may be causative of increased EGFR expression and activity, as recent research has identified an increase in STAT3 signaling in the presence of EGFR/IL6R association and co‐activation (Wang et al ., 2013). STAT1 forms complexes with STAT2 and IRF9 to activate ISGF3G/ISRE (Darnell et al ., 1994); however, STAT3 suppressed STAT1‐dependent gene activation and inhibited STAT1 heterodimer formation (Ho & Ivashkiv, 2006). Furthermore, in tumor cell lines, STAT3 promoted proliferation and cell survival, while STAT1 was antiproliferative and pro‐apoptotic (Pensa et al ., 2009).…”

Section: Discussionmentioning

confidence: 99%

17β-estradiol ameliorates age-associated loss of fibroblast function by attenuating IFN-γ/STAT1-dependent miR-7 upregulation

et al. 2016

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SummaryAge‐related defects in fibroblast differentiation and functionality were previously shown to be associated with impaired hyaluronan (HA) synthase 2 (HAS2) and epidermal growth factor receptor (EGFR) function, as a result of upregulated microRNA‐7 (miR‐7) expression. In aging fibroblasts, inhibiting miR‐7 prevented the dysregulation of the HA‐mediated CD44/EGFR signaling pathway. Here, we investigated transcriptional upregulation of miR‐7 and implicated the age‐associated over‐activation of JAK/STAT1 as a primary candidate. STAT1 binding sites were identified on the putative miR‐7 promoter and stimulation of fibroblasts with the inflammatory cytokine, interferon‐γ (IFN‐γ), significantly increased miR‐7 transcriptional activity and resulted in upregulated miR‐7 and loss of EGFR. Additionally, we demonstrated a role for the anti‐inflammatory steroid, 17β‐estradiol (E2), in the attenuation of miR‐7 expression. E2 stimulation promoted estrogen receptor (ER) interactions with the miR‐7 putative promoter and suppressed miR‐7 expression. E2 also attenuated STAT1 expression and activity. Furthermore, treatments with E2 restored fibroblast functionality, including proliferation, migration and differentiation, key events in effective wound healing. In light of our findings, we propose that the regulation of miR‐7 by pro‐ and anti‐inflammatory mediators plays a wider role than previously thought. The modulation of fibroblast functions and ultimately wound healing by miR‐7 activators or inhibitors could provide realistic targets for the restoration of chronic wound healing capabilities in the elderly.

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Section: Discussionmentioning

confidence: 99%

17β-estradiol ameliorates age-associated loss of fibroblast function by attenuating IFN-γ/STAT1-dependent miR-7 upregulation

et al. 2016

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“…GAF/AAF is formed by homodimerization of the tyrosine phosphorylated Stat1, and ISGF3 is a heterotrimermic complex consisting of the phosphorylated Stat1 and Stat2, and the major DNA binding component p48. In contrast to these two factors, the activation of which does not require de novo protein synthesis, induction of IRF-1 activity by IFNs is controlled by GAF/AAF, whose binding site is found in the IRF-1 promoter (reviewed in Darnell et al 1994;Bluyssen et al 1996;Taniguchi et al 1997). Recent studies using IRF-1, p48 or Stat1 deficient mice revealed that these transcription factors are all critical for the antiviral response to IFNs (Kimura et al 1994;Reis et al 1994;Durbin et al 1996;Kimura et al 1996;Meraz et al 1996).…”

Section: Introductionmentioning

confidence: 99%

Type I interferons are essential mediators of apoptotic death in virally infected cells

et al. 1998

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“…Although not previously linked to chemokine receptor-ligand signaling, expression of several of these genes such as interferon-induced transmembrane protein 2 (IFITM2) and growth hormone inducible transmembrane protein (GHITM) are recognized to be a part of the interferon signaling system that includes Janus kinases and their downstream target STAT proteins [39,40]. IFITM2 is a member of the large 1–8 gene family whose members are strongly induced by both type I (IFNα, IFNβ) and type II (IFNγ) interferons [41,42].…”

Section: Discussionmentioning

confidence: 99%

Identification of genes differentially expressed in T cells following stimulation with the chemokines CXCL12 and CXCL10

Smith

Shaw

et al. 2004

BMC Immunol

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BackgroundChemokines are involved in many biological activities ranging from leukocyte differentiation to neuronal morphogenesis. Despite numerous reports describing chemokine function, little is known about the molecular changes induced by cytokines.MethodsWe have isolated and identified by differential display analysis 182 differentially expressed cDNAs from CXCR3-transfected Jurkat T cells following treatment with CXCL12 or CXCL10. These chemokine-modulated genes were further verified using quantitative RT-PCR and Western blot analysis.ResultsOne hundred and forty-six of the cDNAs were successfully cloned, sequenced, and identified by BLAST. Following removal of redundant and non-informative clones, seventeen mRNAs were found to be differentially expressed post treatment with either chemokine ligand with several representing known genes with established functions. Twenty-one genes were upregulated in these transfected Jurkat cells following both CXCL12 and CXCL10, four genes displayed a discordant response and seven genes were downregulated upon treatment with either chemokine. Identified genes include geminin (GEM), thioredoxin (TXN), DEAD/H box polypeptide 1 (DDX1), growth hormone inducible transmembrane protein (GHITM), and transcription elongation regulator 1 (TCERG1). Subsequent analysis of several of these genes using semi-quantitative PCR and western blot analysis confirmed their differential expression post ligand treatment.ConclusionsTogether, these results provide insight into chemokine-induced gene activation and identify potentially novel functions for known genes in chemokine biology.

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Jak-STAT Pathways and Transcriptional Activation in Response to IFNs and Other Extracellular Signaling Proteins

Cited by 5,511 publications

References 69 publications

17β-estradiol ameliorates age-associated loss of fibroblast function by attenuating IFN-γ/STAT1-dependent miR-7 upregulation

17β-estradiol ameliorates age-associated loss of fibroblast function by attenuating IFN-γ/STAT1-dependent miR-7 upregulation

Type I interferons are essential mediators of apoptotic death in virally infected cells

Identification of genes differentially expressed in T cells following stimulation with the chemokines CXCL12 and CXCL10

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