Testes-specific protease 50 (TSP50) promotes cell proliferation through the activation of the nuclear factor κB (NF-κB) signalling pathway
Testes-specific protease 50 (TSP50) promotes cell proliferation through the activation of the nuclear factor κB (NF-κB) signalling pathway
复制标题
DOI：
10.1042/bj20101780
复制
发表时间：
2011-06-01
影响因子：
4.1
通讯作者：
Li, Yu-Xin
中科院分区：
文献类型：
--
作者：
Song, Zhen-Bo;Bao, Yong-Li;Li, Yu-Xin
TSP 50（testes-specific protease 50，睾丸特异性蛋白酶50）是一种睾丸特异性表达蛋白，在乳腺癌组织中高水平异常表达。这使其成为一个有吸引力的分子标记物和潜在的诊断和治疗靶点;然而，TSP 50的生物学功能仍不清楚。在本研究中，我们表明，在CHO（中国仓鼠卵巢）细胞中过表达TSP 50显着增加细胞增殖和集落形成。机制研究表明，TSP 50可增强TNE α（肿瘤坏死因子α）和PMA诱导的NF-κ B（核因子κ B）反应性报告活性、I κ B（NF-κ B抑制剂）α降解和p65核转位的水平。此外，MDA-MB-231细胞中内源性TSP 50的敲低极大地抑制了NF-κ B活性。免疫共沉淀研究表明，TSP 50与NF-κ B-I κ B α复合物相互作用，但不与IKK（I κ B激酶）α/β-IKK γ复合物相互作用，这表明TSP 50作为一种新型蛋白酶，通过与NE-κ B-I κ B α复合物结合促进I κ B α蛋白的降解。我们的研究结果还表明，TSP 50可以增强NE-κ B靶基因的表达参与细胞增殖。此外，一个显性负性的I κ B突变体，耐蛋白酶体介导的降解显着逆转TSP 50诱导的细胞增殖，集落形成和裸鼠肿瘤形成的过度表达。总之，本研究的结果表明，TSP 50促进细胞增殖，至少部分地，通过激活NF-κ B信号通路。
TSP50 (testes-specific protease 50) is a testis-specific expression protein, which is expressed abnormally at high levels in breast cancer tissues. This makes it an attractive molecular marker and a potential target for diagnosis and therapy; however, the biological function of TSP50 is still unclear. In the present study, we show that overexpression of TSP50 in CHO (Chinese-hamster ovary) cells markedly increased cell proliferation and colony formation. Mechanistic studies have revealed that TSP50 can enhance the level of TNE alpha (tumour necrosis factor alpha)- and PMA-induced NF-kappa B (nuclear factor kappa B)-responsive reporter activity, I kappa B (inhibitor of NF-kappa B) alpha degradation and p65 nuclear translocation. In addition, the knockdown of endogenous TSP50 in MDA-MB-231 cells greatly inhibited NF-kappa B activity. Co-immunoprecipitation studies demonstrated an interaction of TSP50 with the NF-kappa B-I kappa B alpha complex, but not with the IKK (I kappa B kinase) alpha/beta-IKK gamma complex, which suggested that TSP50, as a novel type of protease, promoted the degradation of I kappa B alpha proteins by binding to the NE-kappa B-I kappa B alpha complex. Our results also revealed that TSP50 can enhance the expression of NE-kappa B target genes involved in cell proliferation. Furthermore, overexpression of a dominant-negative I kappa B mutant that is resistant to proteasome-mediated degradation significantly reversed TSP50-induced cell proliferation, colony formation and tumour formation in nude mice. Taken together, the results of the present study suggest that TSP50 promotes cell proliferation, at least partially, through activation of the NF-kappa B signalling pathway.