The transcription factor SP3 drives TNF-α expression in response to Smac mimetics
The transcription factor SP3 drives TNF-α expression in response to Smac mimetics
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DOI：
10.1126/scisignal.aat9563
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发表时间：
2019-01-29
影响因子：
7.3
通讯作者：
Korneluk, Robert G.
中科院分区：
文献类型：
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作者：
Beug, Shawn T.;Cheung, Herman H.;Korneluk, Robert G.
炎症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是重要的。尽管TNF-α的慢性刺激对几种自身免疫性和炎症性疾病的宿主健康有害，但TNF-α-与其名称所暗示的相反-通过促进细胞增殖和存活导致癌症形成。Smac模拟化合物（SMC），凋亡蛋白抑制剂（IAP）的小分子拮抗剂，将TNF-α信号从促进癌细胞存活转变为促进癌细胞死亡。使用全基因组siRNA筛选来鉴定SMC至TNF-α介导的癌细胞死亡所需的因子，我们鉴定转录因子SP3是通过参与核因子-κ B（NF-κ B）转录途径在基础和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表达赋予癌细胞与正常细胞对SMC治疗的不同敏感性。SP3在TNF-α产生和信号传导中的关键作用将有助于我们进一步了解TNF-α生物学，并深入了解与癌症和炎症性疾病相关的机制。
The controlled production and downstream signaling of the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) are important for immunity and its anticancer effects. Although chronic stimulation with TNF-alpha is detrimental to the health of the host in several autoimmune and inflammatory disorders, TNF-alpha -contrary to what its name impliesleads 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-alpha signal from promoting survival to promoting death in cancer cells. Using a genome-wide siRNA screen to identify factors required for SMC-toTNF-alpha-mediated cancer cell death, we identified the transcription factor SP3 as a critical molecule in both basal and SMC-induced production of TNF-alpha by engaging the nuclear factor-kappa B (NF-kappa B) transcriptional pathway. Moreover, the promotion of TNF-alpha expression by SP3 activity confers differential sensitivity of cancer versus normal cells to SMC treatment. The key role of SP3 in TNF-alpha production and signaling will help us further understand TNF-alpha biology and provide insight into mechanisms relevant to cancer and inflammatory disease.