TIFA, an inflammatory signaling adaptor, is tumor suppressive for liver cancer.
TIFA, an inflammatory signaling adaptor, is tumor suppressive for liver cancer.
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TIFA 是一种炎症信号传导接头，可抑制肝癌。
DOI：
10.1038/oncsis.2015.30
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发表时间：
2015-10-26
期刊：
影响因子：
6.2
通讯作者：
Stupack DG
中科院分区：
文献类型：
--
作者：
Shen W;Chang A;Wang J;Zhou W;Gao R;Li J;Xu Y;Luo X;Xiang R;Luo N;Stupack DG
TIFA(肿瘤坏死因子受体相关因子(TRAF)与叉头相关(FHA)结构域的相互作用蛋白)，也称为T2BP，首次通过酵母双杂交筛选得到。TIFA含有一个直接与磷酸苏氨酸和磷酸丝氨酸结合的FHA结构域，以及一个共同的TRAF6结合基序。TIFA介导的TRAF6寡聚和多泛素化介导了肿瘤坏死因子α受体1(TNFaR-I)和白介素1/Toll样受体4(TLR4)通路下游的信号传导。检测TIFA在肝细胞癌组织微阵列中的表达，我们注意到肿瘤中的TIFA反应性明显低于对照样本。我们一致发现，与正常肝对照组相比，肝细胞癌细胞系TIFA表达水平降低。重组TIFA在肝癌细胞中的表达促进了两条独立的凋亡信号通路：P53的诱导和细胞周期的停滞，以及caspase-8和caspase-3的激活。相反，TIFA的非寡聚突变体的表达对细胞的影响最小，抑制TIFA的表达可以保护细胞免受凋亡。与TIFA突变肿瘤相比，携带TIFA高表达肝细胞异种移植瘤的小鼠发展成较小的肿瘤；末端脱氧核苷酸转移酶dUTP缺口末端标记染色显示细胞凋亡增加，增殖减少，反映细胞周期停滞。有趣的是，与细胞死亡相比，P53在抑制细胞增殖方面的作用更大，因为它对TIFA诱导的细胞杀伤来说似乎是可有可无的。这些发现表明，TIFA通过促进细胞死亡而不依赖于P53，在肝癌进展中发挥了新的抑制作用。
TIFA (TNF receptor associated factor (TRAF)-interacting protein with a Forkhead-associated (FHA) domain), also called T2BP, was first identified using a yeast two-hybrid screening. TIFA contains a FHA domain, which directly binds phosphothreonine and phosphoserine, and a consensus TRAF6-binding motif. TIFA-mediated oligomerization and poly-ubiquitinylation of TRAF6 mediates signaling downstream of the Tumor necrosis factor alpha receptor 1 (TNFaR-I) and interleukin-1/Toll-like receptor 4 (TLR4) pathways. Examining TIFA expression in hepatocellular carcinoma (HCC) tissues microarrays, we noted marked decreases TIFA reactivity in tumor versus control samples. In agreement, we found that HCC cell lines show reduced TIFA expression levels versus normal liver controls. Reconstituting TIFA expression in HCC cell lines promoted two independent apoptosis signaling pathways: the induction of p53 and cell cycle arrest, and the activation of caspase-8 and caspase-3. In contrast, the expression of a non-oligomerizing mutant of TIFA impacted cells minimally, and suppression of TIFA expression protected cells from apoptosis. Mice bearing TIFA overexpression hepatocellular xenografts develop smaller tumors versus TIFA mutant tumors; terminal deoxynucleotidyl transferase dUTP nick end labeling staining demonstrates increased cell apoptosis, and decreased proliferation, reflecting cell cycle arrest. Interestingly, p53 has a greater role in decreased proliferation than cell death, as it appeared dispensable for TIFA-induced cell killing. The findings demonstrate a novel suppressive role of TIFA in HCC progression via promotion of cell death independent of p53.