The immediate early genes Fos and Egr1 become STAT1 transcriptional targets in the absence of STAT3

Schiavone, Davide; Avalle, Lidia; Dewilde, Sarah; Poli, Valeria

doi:10.1016/j.febslet.2011.06.020

Cited by 34 publications

(25 citation statements)

References 20 publications

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“…8) phosphorylation (38). Furthermore, recent studies using both atomic force microscopy and X-ray crystallography have directly visualized U-STAT3 binding to GAS elements as an unphosphorylated dimer (37,45 (46). However, the same study also showed that IFN-␥ strongly induces STAT3 Tyr 705 phosphorylation but does not elicit STAT3 binding to the EGR1 promoter, consistent with our results for IL-6 ( Fig.…”

Section: Discussionsupporting

confidence: 82%

Signal Integration and Gene Induction by a Functionally Distinct STAT3 Phosphoform

Waitkus

Chandrasekharan

Willard

et al. 2014

Molecular and Cellular Biology

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Aberrant activation of the ubiquitous transcription factor STAT3 is a major driver of solid tumor progression and pathological angiogenesis. STAT3 activity is regulated by numerous posttranslational modifications (PTMs), including Tyr 705 phosphorylation, which is widely used as an indicator of canonical STAT3 function. Here, we report a noncanonical mechanism of STAT3 activation that occurs independently of Tyr 705 phosphorylation. Using quantitative liquid chromatography-tandem mass spectrometry, we have discovered and characterized a novel STAT3 phosphoform that is simultaneously phosphorylated at Thr

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Section: Discussionsupporting

confidence: 82%

Signal Integration and Gene Induction by a Functionally Distinct STAT3 Phosphoform

Waitkus

Chandrasekharan

Willard

et al. 2014

Molecular and Cellular Biology

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“…22 Indeed, interferon g-like response to IL-6 in the absence of Stat3 was reported together with prolonged Stat1 activation and the induction of Stat1-dependent genes by IL-6. 23,24 In agreement with previous data, 20 the impaired mRNA expression of Socs3 and further decrease in Socs3 protein content on Stat3 deletion in mice expressing JAK2-V617F might also contribute to the increase Stat1 activity in these mice (supplemental Figure 5A-B). In line with our genetic data, we found that inhibiting Stat3 using the Stat3 inhibitor S3I-201 showed a tendency toward increased platelet counts, but this effect was abolished when Stat1 was absent (Figure 7).…”

Section: Org Fromsupporting

confidence: 80%

Deletion of Stat3 in hematopoietic cells enhances thrombocytosis and shortens survival in a JAK2-V617F mouse model of MPN

Grisouard

Shimizu

Duek

et al. 2015

Blood

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“…In most cell types, STAT1 and STAT3 play opposing roles, although the mechanisms are still speculative and include the formation of nonfunctional STAT1/STAT3 heterodimers, which disrupt nuclear transport [8], competition for common receptor docking sites, and displacement of STAT3 from its target promoters by STAT1 [14].…”

Section: Discussionmentioning

confidence: 99%

“…45: 2834-2846 Immunity to infection 2843 demonstrated a decreased level of binding. As diminished STAT3 binding to endogenous DNA targets is crucial for a mechanistic understanding of reduced transcriptional activity, future work will focus on the analysis of STAT3-mediated target sequence binding to additional endogenous STAT3-dependent promoters as well as exploring the hypothesis that impaired binding may be due to STAT1 displacing STAT3 from its target promoters as the mechanism leading to Th17 deficiency [14]. Lack of these experiments clearly limits our understanding of the underlying mechanisms presented in this publication and further clarification is planned for our future work.…”

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confidence: 99%

Gain‐of‐function STAT1 mutations impair STAT3 activity in patients with chronic mucocutaneous candidiasis (CMC)

et al. 2015

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Signal transducer and activator of transcription 3 (STAT3) triggered production of Th-17 cytokines mediates protective immunity against fungi. Mutations affecting the STAT3/interleukin 17 (IL-17) pathway cause selective susceptibility to fungal (Candida) infections, a hallmark of chronic mucocutaneous candidiasis (CMC). In patients with autosomal dominant CMC, we and others previously reported defective Th17 responses and underlying gain-of-function (GOF) STAT1 mutations, but how this affects STAT3 function leading to decreased IL-17 is unclear. We also assessed how GOF-STAT1 mutations affect STAT3 activation, DNA binding, gene expression, cytokine production, and epigenetic modifications. We excluded impaired STAT3 phosphorylation, nuclear translocation, and sequestration of STAT3 into STAT1/STAT3 heterodimers and confirm significantly reduced transcription of STAT3-inducible genes (RORC/IL-17/IL-22/IL-10/c-Fos/SOCS3/cMyc) as likely underlying mechanism. STAT binding to the high affinity sis-inducible element was intact but binding to an endogenous STAT3 DNA target was impaired. Reduced STAT3-dependent gene transcription was reversed by inhibiting STAT1 activation with fludarabine or enhancing histone, but not STAT1 or STAT3 acetylation with histone deacetylase (HDAC) inhibitors trichostatin A or ITF2357. Silencing HDAC1, HDAC2, and HDAC3 indicated a role for HDAC1 and 2. Reduced STAT3-dependent gene transcription underlies low Th-17 responses in GOF-STAT1 CMC, which can be reversed by inhibiting acetylation, offering novel targets for future therapies.Correspondence: Dr. Desa Lilic e-mail: desa.lilic@ncl.ac.uk * Both authors contributed equally to this work.C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2015. 45: 2834-2846 Immunity to infection 2835 Keywords: Chronic mucocutaneous candidiasis (CMC) HDAC inhibitors IL-17 STAT1 gain-of-function mutation STAT3 STAT1 inhibitorsAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionPatients with chronic mucocutaneous candidiasis (CMC) present with recurrent or persistent infections of the skin, nails, and mucosal membranes with the fungus Candida [1]. Candida is an opportunistic yeast that does not cause disease in healthy individuals despite inhabiting bodily surfaces as it is controlled by immune mechanisms, specifically Th-17 cells and cytokines produced by them [2]. Mucosal infections with Candida species indicate an underlying T-cell deficiency, which is most often secondary to immunosuppressive and/or chemotherapy, antibiotics, biological therapies, HIV, or other permissive circumstances. However, in rare patients, these infections present as a severe syndrome coined CMC, a primary immune deficiency in which the underlying cause is a genetic mutation affecting immune pathways essential for fungal protection [3]. Research in primary immune deficiency patients with isolated CMC has documented the crucial role of the signal transducer and activator of tra...

show abstract

The immediate early genes Fos and Egr1 become STAT1 transcriptional targets in the absence of STAT3

Cited by 34 publications

References 20 publications

Signal Integration and Gene Induction by a Functionally Distinct STAT3 Phosphoform

Signal Integration and Gene Induction by a Functionally Distinct STAT3 Phosphoform

Deletion of Stat3 in hematopoietic cells enhances thrombocytosis and shortens survival in a JAK2-V617F mouse model of MPN

Gain‐of‐function STAT1 mutations impair STAT3 activity in patients with chronic mucocutaneous candidiasis (CMC)

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