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The transcription factor SP3 drives TNF-α expression in response to Smac mimetics
Science Signaling ( IF 7.3 ) Pub Date : 2019-01-29 , DOI: 10.1126/scisignal.aat9563
Shawn T. Beug 1, 2 , Herman H. Cheung 1 , Tarun Sanda 1, 2 , Martine St-Jean 1 , Caroline E. Beauregard 1, 2 , Hapsatou Mamady 1 , Stephen D. Baird 1 , Eric C. LaCasse 1 , Robert G. Korneluk 1, 2
Affiliation  

The controlled production and downstream signaling of the inflammatory cytokine tumor necrosis factor–α (TNF-α) are important for immunity and its anticancer effects. Although chronic stimulation with TNF-α is detrimental to the health of the host in several autoimmune and inflammatory disorders, TNF-α—contrary to what its name implies—leads to cancer formation by promoting cell proliferation and survival. Smac mimetic compounds (SMCs), small-molecule antagonists of inhibitor of apoptosis proteins (IAPs), switch the TNF-α signal from promoting survival to promoting death in cancer cells. Using a genome-wide siRNA screen to identify factors required for SMC–to–TNF-α–mediated cancer cell death, we identified the transcription factor SP3 as a critical molecule in both basal and SMC-induced production of TNF-α by engaging the nuclear factor κB (NF-κB) transcriptional pathway. Moreover, the promotion of TNF-α expression by SP3 activity confers differential sensitivity of cancer versus normal cells to SMC treatment. The key role of SP3 in TNF-α production and signaling will help us further understand TNF-α biology and provide insight into mechanisms relevant to cancer and inflammatory disease.



中文翻译:

转录因子SP3响应Smac模拟物驱动TNF-α表达

炎性细胞因子肿瘤坏死因子-α(TNF-α)的受控产生和下游信号传导对于免疫及其抗癌作用至关重要。尽管在几种自身免疫和炎性疾病中,用TNF-α进行慢性刺激会损害宿主的健康,但TNF-α与其名称相反,却通过促进细胞增殖和存活而导致癌症形成。Smac模拟化合物(SMCs)是凋亡蛋白抑制剂(IAPs)的小分子拮抗剂,可将TNF-α信号从促进生存转变为促进癌细胞死亡。使用全基因组siRNA筛查来确定SMC转化为TNF-α介导的癌细胞死亡所需的因子,我们通过参与核因子κB(NF-κB)转录途径,将转录因子SP3确定为基础和SMC诱导的TNF-α产生中的关键分子。此外,通过SP3活性促进TNF-α的表达使癌症细胞与正常细胞对SMC的治疗具有不同的敏感性。SP3在TNF-α产生和信号转导中的关键作用将帮助我们进一步了解TNF-α生物学,并深入了解与癌症和炎性疾病相关的机制。

更新日期:2019-01-30
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