STAT3-mediated Coincidence Detection Regulates Noncanonical Immediate Early Gene Induction

Waitkus, Matthew S.; Chandrasekharan, Unnikrishnan M.; Willard, Belinda; Haque, S. Jaharul; DiCorleto, Paul E.

doi:10.1074/jbc.m112.428516

Cited by 11 publications

(15 citation statements)

References 66 publications

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“…Depletion of STAT3 by RNAi completely inhibited synergistic induction of Mcl1 (Fig. 5D), demonstrating that STAT3 is critical for EGFR/PAR-1 cross talk, consistent with our previously published results for EGR1 induction (25). Inducible expression of Mcl1 was reduced ϳ50% when GSK-3␣/␤ were depleted by RNAi, consistent with our hypothesis that GSK-3␣/␤ positively regulate STAT3 activity ( Fig.…”

Section: Resultssupporting

confidence: 81%

“…GSK-3␣/␤ phosphorylate STAT3 to generate a doubly modified phosphoform. We previously reported that GSK-3␣/␤ positively regulated STAT3 Ser 727 phosphorylation and STAT3-dependent gene expression in EC (25). Therefore, we investigated the extent to which GSK-3␣/␤ regulate the stimulus-inducible generation of specific STAT3 phosphoforms downstream of EGFR/PAR-1 signaling.…”

Section: Resultsmentioning

confidence: 99%

“…Chromatin-protein complexes were immunoprecipitated overnight with an anti-STAT3 antibody, and genomic DNA was purified using DNA PrepEase columns (Affymetrix). Purified genomic DNA was analyzed by quantitative real-time PCR using primers flanking the upstream GAS element in the EGR1 promoter (25): forward primer, 5=-CAGGAGGAGC CTTCCCTTCCCG-3=; reverse primer, 5=-CTGGGGCCGAACGCAACA G-3=. The data were normalized relative to the amount of input DNA for each sample and expressed as the fold change relative to the untreated control sample.…”

Section: Methodsmentioning

confidence: 99%

“…Luciferase reporter assays were performed using a 2.1-kb fragment of the EGR1 promoter, as previously described (25). Briefly, luciferase assays were performed by transfecting EC with EGR1 promoter reporter 24 h prior to treatment.…”

Section: Methodsmentioning

confidence: 99%

“…We previously reported that STAT3 is a critical signal integrator downstream of coincident EGFR and protease-activated receptor 1 (PAR-1) signaling in vascular endothelial cells (EC) (25). In this context, glycogen synthase kinase 3␣ and -␤ (GSK-3␣/␤)-dependent phosphorylation of STAT3 Ser 727 is required to trigger inducible expression of the transcription factor early growth response 1 (EGR1).…”

mentioning

confidence: 99%

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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: Resultssupporting

confidence: 81%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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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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Potentiation of cancerous progression by LISCH7 via direct stimulation of TGFB1 transcription in triple‐negative breast cancer

Tang

Zhou

Liu

et al. 2020

J of Cellular Biochemistry

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As an aggressive breast cancer (BCa) subtype, triple‐negative breast cancer (TNBC) responses poorly to chemotherapy and endocrine therapy, and usually has a worse prognosis. This is largely due to the lack of specific therapeutic targets, laying claim to an imperious demand to clarify the key signaling pathways potentiating TNBC progression. Herein, we report that expression levels of the liver‐specific bHLH‐Zip transcription factor (LISCH7), a recently identified key player in cancerous progression, preferentially enriched in TNBC in comparison with other BCa subtypes, and this upregulation was observed to be correlated to a poor survival outcome in patients with TNBC. Ablation of LISCH7 in TNBC cells impaired cell proliferation, reduced cell invasiveness, and enhanced sensitivity to the first‐line chemotherapeutic drug docetaxel at both in vitro and in vivo levels. Importantly, concurrent induction of TGFB1, the gene encoding transforming growth factor‐β1 (TGF‐β1), an essential multipluripotent regulator of TNBC, was accompanied with these alterations in cancerous properties. We further showed that LISCH7 could directly bind to the TGFB1 promoter and stimulate TGFB1 transcription in TNBC cells. The recruitment of LISCH7 onto the TGFB1 chromatin and transactivation of TGFB1 were substantially augmented by treatment with the exogenous TGF‐β1 in a time‐ and dose‐dependent manner. Collectively, these findings suggest that LISCH7 and TGF‐β1 form a reciprocal positive regulatory loop and cooperatively regulate cancerous progression in TNBC cells. Thus, simultaneous inhibition of both LISCH7 and TGF‐β1 signaling may represent a more effective approach to counteract advanced TNBC.

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Vascular Endothelial Cells Produce Coagulation Factors That Control Their Growth via Joint Protease-Activated Receptor and C5a Receptor 1 (CD88) Signaling

Cao

Strainic

Counihan

et al. 2022

The American Journal of Pathology

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STAT3-mediated Coincidence Detection Regulates Noncanonical Immediate Early Gene Induction

Cited by 11 publications

References 66 publications

Signal Integration and Gene Induction by a Functionally Distinct STAT3 Phosphoform

Signal Integration and Gene Induction by a Functionally Distinct STAT3 Phosphoform

Potentiation of cancerous progression by LISCH7 via direct stimulation of TGFB1 transcription in triple‐negative breast cancer

Vascular Endothelial Cells Produce Coagulation Factors That Control Their Growth via Joint Protease-Activated Receptor and C5a Receptor 1 (CD88) Signaling

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