Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan 70101, Taiwan.
J Biol Chem. 2012 Jun 29;287(27):22533-48. doi: 10.1074/jbc.M111.335331. Epub 2012 May 4.
The nucleolar 58-kDa microspherule protein (MSP58) protein is a candidate oncogene implicated in modulating cellular proliferation and malignant transformation. In this study, we show that knocking down MSP58 expression caused aneuploidy and led to apoptosis, whereas ectopic expression of MSP58 regulated cell proliferation in a context-dependent manner. Specifically, ectopic expression of MSP58 in normal human IMR90 and Hs68 diploid fibroblasts, the H184B5F5/M10 mammary epithelial cell line, HT1080 fibrosarcoma cells, primary mouse embryonic fibroblasts, and immortalized NIH3T3 fibroblasts resulted in induction of premature senescence, an enlarged and flattened cellular morphology, and increased senescence-associated β-galactosidase activity. MSP58-driven senescence was strictly dependent on the presence of functional p53 as revealed by the fact that normal cells with p53 knockdown by specific shRNA or cells with a mutated or functionally impaired p53 pathway were effective in bypassing MSP58-induced senescence. At least two senescence mechanisms are induced by MSP58. First, MSP58 activates the DNA damage response and p53/p21 signaling pathways. Second, MSP58, p53, and the SWI/SNF chromatin-remodeling subunit Brahma-related gene 1 (BRG1) form a ternary complex on the p21 promoter and collaborate to activate p21. Additionally, MSP58 protein levels increased in cells undergoing replicative senescence and stress-induced senescence. Notably, the results of analyzing expression levels of MSP58 between tumors and matched normal tissues showed significant changes (both up- and down-regulation) in its expression in various types of tumors. Our findings highlight new aspects of MSP58 in modulating cellular senescence and suggest that MSP58 has both oncogenic and tumor-suppressive properties.
核仁 58kDa 微球体蛋白（MSP58）是一种候选癌基因，参与调节细胞增殖和恶性转化。在这项研究中，我们发现敲低 MSP58 表达会导致非整倍体并导致细胞凋亡，而 MSP58 的异位表达以依赖于上下文的方式调节细胞增殖。具体而言，在正常的人 IMR90 和 Hs68 二倍体成纤维细胞、H184B5F5/M10 乳腺上皮细胞系、HT1080 纤维肉瘤细胞、原代小鼠胚胎成纤维细胞和永生化 NIH3T3 成纤维细胞中异位表达 MSP58 会诱导过早衰老、细胞形态增大和平坦化以及衰老相关β-半乳糖苷酶活性增加。MSP58 驱动的衰老严格依赖于功能 p53 的存在，这一事实揭示了通过特定 shRNA 敲低 p53 的正常细胞或具有突变或功能受损 p53 途径的细胞有效地绕过了 MSP58 诱导的衰老。至少有两种衰老机制是由 MSP58 诱导的。首先，MSP58 激活了 DNA 损伤反应和 p53/p21 信号通路。其次，MSP58、p53 和染色质重塑亚基 SWI/SNF 中的 Brahma 相关基因 1（BRG1）在 p21 启动子上形成三元复合物，并协同激活 p21。此外，在经历复制性衰老和应激诱导性衰老的细胞中，MSP58 蛋白水平增加。值得注意的是，在分析肿瘤和匹配的正常组织之间 MSP58 的表达水平时，发现其在各种类型的肿瘤中表达有显著变化（上调和下调）。我们的研究结果突出了 MSP58 在调节细胞衰老方面的新方面，并表明 MSP58 具有致癌和抑癌特性。
