Kim Patrick Y, Tan Owen, Liu Bing, Trahair Toby, Liu Tao, Haber Michelle, Norris Murray D, Marshall Glenn M, Cheung Belamy B
Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick 2031, Sydney, Australia.
Kids Cancer Centre, Sydney Children's Hospital, Randwick 2031, Sydney, Australia.
Cancer Lett. 2016 May 1;374(2):315-23. doi: 10.1016/j.canlet.2016.02.021. Epub 2016 Feb 20.
Tripartite Motif-containing protein 16 (TRIM16) is a member of a large family of tripartite motif (TRIM) proteins, that has been implicated in the pathogenesis of multiple cancers. However, the mechanism by which TRIM16 acts as a tumour suppressor is currently unknown. We used the versatile yeast two-hybrid assay on a cDNA library from human testes, which has relative high TRIM16 expression, to identify potential TRIM16-binding proteins. We identified transactive response DNA-binding protein 43 (TDP43) as a novel TRIM16 binding protein. Co-immunoprecipitation assay demonstrated that TDP43 bound TRIM16 in neuroblastoma and breast cancer cells. Enforced over-expression of TRIM16 increased the protein half-life of TDP43, through the inhibition of the proteosomal degradation pathway. High levels of TRIM16 and TDP43 are associated with good prognosis in both human neuroblastoma and breast cancer tissues. Importantly, we found TDP43 expression was required for TRIM16-induced inhibition of neuroblastoma and breast cancer cell growth and the repressive effect of TRIM16 on cell cycle regulatory proteins, E2F1 and pRb. Taken together, our data suggest that TRIM16 and TDP43 are both good prognosis indicators; also we showed that TRIM16 inhibits cancer cell viability by a novel mechanism involving interaction and stabilisation of TDP43 with consequent effects on E2F1 and pRb proteins.
含三联基序蛋白16（TRIM16）是三联基序（TRIM）蛋白大家族的成员之一，与多种癌症的发病机制有关。然而，TRIM16作为肿瘤抑制因子发挥作用的机制目前尚不清楚。我们利用酵母双杂交技术，对来自人睾丸的cDNA文库（其中TRIM16表达相对较高）进行检测，以鉴定潜在的TRIM16结合蛋白。我们鉴定出反式激活反应DNA结合蛋白43（TDP43）是一种新的TRIM16结合蛋白。免疫共沉淀实验表明，TDP43在神经母细胞瘤和乳腺癌细胞中与TRIM16结合。TRIM16的强制过表达通过抑制蛋白酶体降解途径，延长了TDP43的蛋白质半衰期。在人神经母细胞瘤和乳腺癌组织中，高水平的TRIM16和TDP43与良好的预后相关。重要的是，我们发现TRIM16诱导的神经母细胞瘤和乳腺癌细胞生长抑制以及TRIM16对细胞周期调节蛋白E2F1和pRb的抑制作用需要TDP43的表达。综上所述，我们的数据表明，TRIM16和TDP43都是良好的预后指标；我们还表明，TRIM16通过一种新的机制抑制癌细胞活力，该机制涉及TDP43的相互作用和稳定，从而对E2F1和pRb蛋白产生影响。
