Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NFκB

Yang, Jinbo; Liao, Xudong; Agarwal, Megha; Barnes, Laura; Auron, Philip E.; Stark, George R.

doi:10.1101/gad.1553707

Cited by 546 publications

(544 citation statements)

References 54 publications

(54 reference statements)

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“…Consistent with previous reports [27][28][29][30], STAT3 and RELA were coimmunoprecipitated from 293-OBRb cells (Fig. 5a).…”

Section: Resultssupporting

confidence: 93%

“…Nonetheless, we tested the second hypothesis, which may work in parallel with the first one, by examining the pSTAT3 levels in the cytosolic and nuclear fractions of leptin-stimulated 293-OBRb cells. Although STAT3 may directly interact with RELA [27][28][29][30] (also see Fig. 5a), increasing amounts of RELA did not affect pSTAT3 nuclear translocation (Fig.…”

Section: Resultsmentioning

confidence: 80%

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Nuclear factor κB (NF-κB) suppresses food intake and energy expenditure in mice by directly activating the Pomc promoter

Shi

Wang

et al. 2013

Diabetologia

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Aims/hypothesis While chronic low-grade inflammation is associated with obesity, acute inflammation reduces food intake and leads to negative energy balance. Although both types of inflammation activate nuclear factor κB (NF-κB) signalling, it remains unclear how NF-κB activation results in opposite physiological responses in the two types of inflammation. The goal of this study was to address this question, and to understand the link between inflammation and leptin signalling.Methods We studied the ability of NF-κB to modulate Pomc transcription, and how it impinges on signal transducer and activator of transcription 3 (STAT3)-mediated leptin signalling by using a combination of animal models, biochemical assays and molecular biology. Results We report that suppression of food intake and physical movement with acute inflammation is not dependent on STAT3 activation in pro-opiomelanocortin (POMC) neurons. Under these conditions, activated NF-κB independently leads to increased Pomc transcription. Electrophoretic mobility shift assay and chromatin immunoprecipitation (ChIP) experiments reveal that NF-κB v-rel reticuloendotheliosis viral oncogene homologue A (avian) (RELA [also known as p65]) binds to the Pomc promoter region between −138 and −88 bp, which also harbours the trans-acting transcription factor 1 (SP1) binding site. We found significant changes in the methylation pattern at this region and reduced Pomc activation under chronic inflammation induced by a high-fat diet. Furthermore, RELA is unable to bind and activate transcription when the Pomc promoter is methylated. Finally, RELA binds to STAT3 and inhibits STAT3-mediated promoter activity, suggesting that RELA, possibly together with forkhead box-containing protein 1 (FOXO1), may prevent STAT3-mediated leptin activation of the Pomc promoter. Conclusions/interpretation Our study provides a mechanism for the involvement of RELA in the divergent regulation of energy homeostasis in acute and chronic inflammation.

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“…Consistent with previous reports [27][28][29][30], STAT3 and RELA were coimmunoprecipitated from 293-OBRb cells (Fig. 5a).…”

Section: Resultssupporting

confidence: 93%

Section: Resultsmentioning

confidence: 80%

Nuclear factor κB (NF-κB) suppresses food intake and energy expenditure in mice by directly activating the Pomc promoter

Shi

Wang

et al. 2013

Diabetologia

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“…First, the members of NF-κB like RelA can physiologically interact with STAT3 and their association can modify their transcriptional activity (Yu et al, 2002;Lee et al, 2009). Second, as two important transcriptional factors, NF-κB and STAT3 cooperatively bind at a subset of gene promoters to collaboratively induce their target genes expression (Yang et al, 2007). Third, many cytokines like IL-6 induced by NF-κB or STAT3 can feedback to induce STAT3 and NF-κB activation (Gao et al, 2007;Sansone et al, 2007;Grivennikov and Karin, 2008).…”

Section: Stats Signaling Transduction Pathwaymentioning

confidence: 99%

NF-κB and STAT3 signaling pathways collaboratively link inflammation to cancer

2013

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“…Phosphorylated STAT3 upregulates RANTES expression RANTES is a STAT3 target gene (40,41). To investigate the role of STAT3 activation in RANTES expression, we used the JAK2 inhibitor, AG490, which suppresses constitutive STAT3 activation.…”

Section: Rantes-mediated Stat3 Activationmentioning

confidence: 99%

STAT3-RANTES Autocrine Signaling Is Essential for Tamoxifen Resistance in Human Breast Cancer Cells

Lee

et al. 2013

Molecular Cancer Research

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The acquisition of tamoxifen resistance is a major therapeutic problem in breast cancer. We developed a tamoxifen-resistant MCF-7 (TRM-7) cell line to elucidate the molecular mechanisms and factors associated with acquisition of such resistance. We showed that phosphorylation of STAT3 at tyrosine 705 (Y705) and RANTES expression are increased in response to tamoxifen in human breast cancer cells. On the basis of these results, we hypothesize that upregulated STAT3 phosphorylation and RANTES may be correlated with the development of drug resistance. Here, we showed that STAT3 and RANTES contribute to the maintenance of drug resistance. STAT3 phosphorylation is constitutively retained via a RANTES autocrine loop, which in turn upregulates antiapoptotic signals in TRM-7 cells. STAT3-RANTES autocrine signaling affected expression of anti-apoptotic BCL-2 family genes and prevented TRM-7 cells from undergoing programmed cell death by inhibiting PARP and caspase-9 cleavage. Subsequently, blockade of STAT3 and RANTES in TRM-7 cells resulted in reduction of antiapoptotic signals, which was rescued by exogenous RANTES treatment; drug resistance was also restored. Taken together, our results suggested that STAT3-RANTES autocrine signaling is essential for maintenance of drug resistance and inhibition of programmed cell death. These mechanisms of STAT3-RANTES autocrine signaling suggest a novel strategy for management of patients with tamoxifen-resistant tumors. Mol Cancer Res; 11(1); 31-42. Ó2012 AACR. IntroductionBreast cancer is the second most common cancer worldwide after lung cancer, the fifth most common cause of cancer death, and the leading cause of cancer death in women. The global burden of breast cancer exceeds that of all other cancers, and its incidence is increasing (1). In women younger than 50 years with breast cancer, chemotherapy increases the 15-year survival rate by 10%,

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Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NFκB

Abstract: [Keywords: Gene chip; gene transcription; IL-6; Jak-Stat; NF B] Supplemental material is available at http://www.genesdev.org.

Cited by 546 publications

References 54 publications

Nuclear factor κB (NF-κB) suppresses food intake and energy expenditure in mice by directly activating the Pomc promoter

Nuclear factor κB (NF-κB) suppresses food intake and energy expenditure in mice by directly activating the Pomc promoter

NF-κB and STAT3 signaling pathways collaboratively link inflammation to cancer

STAT3-RANTES Autocrine Signaling Is Essential for Tamoxifen Resistance in Human Breast Cancer Cells

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