ArticleCellular signalling2014
Inducible STAT3 NH2 terminal mono-ubiquitination promotes BRD4 complex formation to regulate apoptosis.
Article in Cellular signalling, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 52 citations in OpenAlex.
- Inhibition of BRD4 attenuated IFNγ-induced apoptosis in colorectal cancer organoids.BMC cancer · 2025Article
- A combinatorial screening protocol for identifying novel and highly potent dual-target inhibitor of BRD4 and STAT3 for kidney cancer therapy.Frontiers in pharmacology · 2025Article
- IκB kinase-α coordinates BRD4 and JAK/STAT signaling to subvert DNA damage-based anticancer therapy.The EMBO journal · 2023Article
- Article
- Regulation of Cell Plasticity by Bromodomain and Extraterminal Domain (BET) Proteins: A New Perspective in Glioblastoma Therapy.International journal of molecular sciences · 2023Review
- Bromodomain-containing protein 4 (BRD4): a key player in inflammatory bowel disease and potential to inspire epigenetic therapeutics.Expert opinion on therapeutic targets · 2023Review
- BET proteins are essential for the specification and maintenance of the epiblast lineage in mouse preimplantation embryos.BMC biology · 2022Article
- Structural exploration with AlphaFold2-generated STAT3α structure reveals selective elements in STAT3α-GRIM-19 interactions involved in negative regulation.Scientific reports · 2021Article
- Regulation of STAT3 and its role in cardioprotection by conditioning: focus on non-genomic roles targeting mitochondrial function.Basic research in cardiology · 2021Review
- BRD4 targeting nanotherapy prevents lipopolysaccharide induced acute respiratory distress syndrome.International journal of pharmaceutics · 2021Article
- DGG-100629 inhibits lung cancer growth by suppressing the NFATc1/DDIAS/STAT3 pathway.Experimental & molecular medicine · 2021Article
- The BET family in immunity and disease.Signal transduction and targeted therapy · 2021Review
- The Multifaced Role of STAT3 in Cancer and Its Implication for Anticancer Therapy.International journal of molecular sciences · 2021Review
- Acute Systemic Inflammatory Response Alters Transcription Profile of Genes Related to Immune Response and CaInternational journal of molecular sciences · 2020Article
- Redox Regulation of STAT1 and STAT3 Signaling.International journal of molecular sciences · 2020Review
- Epigenetic Modulation by Apabetalone Counters Cytokine-Driven Acute Phase ResponseCardiovascular therapeutics · 2020Article
- Nicotine Upregulates the Level of Mcl-1 through STAT3 in H1299 Cells.Journal of Cancer · 2020Article
- Opportunities and challenges of co-targeting epidermal growth factor receptor and autophagy signaling in non-small cell lung cancer.Oncology letters · 2019Review
- PTPN9 induces cell apoptosis by mitigating the activation of Stat3 and acts as a tumor suppressor in colorectal cancer.Cancer management and research · 2019Article
- Article
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Signal Transducers and Activator of Transcription-3 (STAT3) are latent transcription factors that are regulated by post-translational modifications (PTMs) in response to cellular activation by the IL-6 superfamily of cytokines to regulate cell cycle progression and/or apoptosis. Here we observe that STAT3 is inducibly mono-ubiquitinated and investigate its consequences. Using domain mapping and highly specific selected reaction monitoring-mass spectrometric assays, we identify lysine (K) 97 in its NH2-terminal domain as the major mono-ubiquitin conjugation site. We constructed a mono-ubiquitinated mimic consisting of a deubiquitinase-resistant monomeric ubiquitin fused to the NH2 terminus of STAT3 (ubiquitinated-STAT3 FP). In complex assays of ectopically expressed ubi-STAT3-FP, we observed enhanced complex formation with bromodomain-containing protein 4 (BRD4), a component of the activated positive transcriptional elongation factor (P-TEFb) complex. Chromatin immunoprecipitation experiments in STAT3(+/-) and STAT3(-/-) MEFs showed BRD4 recruitment to STAT3-dependent suppressor of cytokine signaling-3 gene (SOCS3). The effect of a selective small molecule inhibitor of BRD4, JQ1, to inhibit SOCS3 expression demonstrated the functional role of BRD4 for STAT3-dependent transcription. Additionally, ectopic ubiquitinated-STAT3 FP expression upregulated BCL2, BCL2L1, APEX1, SOD2, CCND1 and MYC expression indicating the role of ubiquitinated STAT3 in anti-apoptosis and cellular proliferation. Finally we observed that ubiquitinated-STAT3 FP suppressed TNFα-induced apoptotic cell death, indicating the functional importance of mono-ubiquitinated STAT3 in antiapoptotic gene expression. We conclude that STAT3 mono-ubiquitination is a key trigger in BRD4-dependent antiapoptotic and pro-proliferative gene expression programs. Thus, inhibiting the STAT3 mono-ubiquitination-BRD4 pathway may be a novel therapeutic target for the treatment of STAT3-dependent proliferative diseases.
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