A novel IL-17 signaling pathway controlling keratinocyte proliferation and tumorigenesis via the TRAF4-ERK5 axis.
A novel IL-17 signaling pathway controlling keratinocyte proliferation and tumorigenesis via the TRAF4-ERK5 axis.
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DOI：
10.1084/jem.20150204
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发表时间：
2015-09-21
期刊：
影响因子：
--
通讯作者：
Li X
中科院分区：
文献类型：
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作者：
Wu L;Chen X;Zhao J;Martin B;Zepp JA;Ko JS;Gu C;Cai G;Ouyang W;Sen G;Stark GR;Su B;Vines CM;Tournier C;Hamilton TA;Vidimos A;Gastman B;Liu C;Li X
Wu等报道了一种新的IL-17介导的级联反应，其通过IL-17 R-TRAF 4-ERK 5轴直接刺激小鼠中的角质形成细胞增殖和皮肤肿瘤形成。尽管IL-17正在成为癌症促进和进展中的重要细胞因子，但其基本分子机制仍不清楚。以前的研究表明，IL-17（IL-17 A）维持有利于肿瘤形成的慢性炎症微环境。在这里，我们报告了一种新的IL-17介导的级联通过IL-17 R-Act 1-TRAF 4-MEKK 3-ERK 5正电路，直接刺激角质形成细胞增殖和肿瘤形成。尽管该轴决定了靶基因Steap 4（用于细胞代谢和增殖的金属还原酶）和p63（用于表皮干细胞增殖的转录因子）的表达，但Steap 4是表皮中p63+基底细胞的IL-17诱导的持续扩增所需的。P63（Traf 4启动子的正性转录因子）诱导角质形成细胞中的TRAF 4表达。因此，IL-17诱导的Steap 4-p63表达通过p63介导的TRAF 4表达形成正反馈环，驱动TRAF 4-ERK 5轴的IL-17依赖性持续激活，用于角质形成细胞增殖和肿瘤形成。
Wu et al. report a novel IL-17–mediated cascade via the IL-17R–TRAF4–ERK5 axis that directly stimulates keratinocyte proliferation and skin tumor formation in mice. Although IL-17 is emerging as an important cytokine in cancer promotion and progression, the underlining molecular mechanism remains unclear. Previous studies suggest that IL-17 (IL-17A) sustains a chronic inflammatory microenvironment that favors tumor formation. Here we report a novel IL-17–mediated cascade via the IL-17R–Act1–TRAF4–MEKK3–ERK5 positive circuit that directly stimulates keratinocyte proliferation and tumor formation. Although this axis dictates the expression of target genes Steap4 (a metalloreductase for cell metabolism and proliferation) and p63 (a transcription factor for epidermal stem cell proliferation), Steap4 is required for the IL-17–induced sustained expansion of p63+ basal cells in the epidermis. P63 (a positive transcription factor for the Traf4 promoter) induces TRAF4 expression in keratinocytes. Thus, IL-17–induced Steap4-p63 expression forms a positive feedback loop through p63-mediated TRAF4 expression, driving IL-17–dependent sustained activation of the TRAF4–ERK5 axis for keratinocyte proliferation and tumor formation.