Regulation of Replicative and Stress-Induced Senescence by RSK4, which is Down-regulated in Human Tumors
Regulation of Replicative and Stress-Induced Senescence by RSK4, which is Down-regulated in Human Tumors
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DOI：
10.1158/1078-0432.ccr-08-3159
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发表时间：
2009-07-15
影响因子：
11.5
通讯作者：
Ramon y Cajal, Santiago
中科院分区：
文献类型：
--
作者：
Lopez-Vicente, Laura;Armengol, Gemma;Ramon y Cajal, Santiago
目的：衰老及其生化途径的控制是了解细胞转化的关键因素。在大的RNA干扰筛选中，发现RSK 4基因与p53依赖性阻滞相关。本研究的目的是探讨RSK 4作为抑癌基因的潜在作用。实验设计：RSK 4的表达测定在30个结肠癌和20个肾癌，并在7个结肠腺瘤的定量实时PCR和免疫印迹。用RSK 4 cDNA和/或shRNA感染两种HCT 116结肠癌细胞系（p53 wt和p53 null）、IMR 90人成纤维细胞和表达EIIA的IMR 90细胞。结果：30例结肠癌、20例肾细胞癌和7例结肠腺瘤中分别有27例、16例和6例RSK 4基因表达下调（P < 0.001），肾细胞癌中RSK 4基因表达下调（P <0.01），结肠腺瘤中RSK 4基因表达下调（P < 0.01）。在正常成纤维细胞和恶性结肠癌细胞系中，RSK 4的体外过表达诱导细胞停滞和衰老特征。有趣的是，在这些细胞系中，RSK 4 mRNA水平在复制和应激诱导的衰老中均增加。此外，通过RSK 4 shRNA部分永生化的IMR 90和具有该短发夹RNA的HCT 116对顺铂治疗更有抗性。最后，表达E1 A或Rb短干扰RNA的细胞抵抗RSK 4介导的senescence.Conclusion：这些结果支持的概念，RSK 4可能是一个重要的肿瘤抑制基因，通过调节衰老诱导和促进细胞增殖控制在结肠癌和肾细胞癌。
Purpose: The control of senescence and its biochemical pathways is a crucial factor for understanding cell transformation. In a large RNA interference screen, the RSK4 gene was found to be related to p53-dependent arrest. The purpose of the present study was to investigate the potential role of RSK4 as a tumor suppressor gene.Experimental Design: RSK4 expression was determined by quantitative real-time PCR and immunoblot in 30 colon and 20 renal carcinomas, and in 7 colon adenomas. Two HCT116 colon carcinoma cell lines (p53 wt and p53 null), IMR90 human fibroblasts, and EIIA-expressing IMR90 cells were infected with RSK4 cDNA and/or shRNA. RSK4 expression levels were analyzed in HCT116 p53 wt or p53 null and IMR90 after senescence induction by quantitative real-time PCR and Western blot.Results: The RSK4 gene was down-regulated in 27 of 30 colon carcinomas (P < 0.001), 16 of 20 renal cell carcinomas (P < 0.01), and 6 of 7 colon adenomas (P < 0.01). In vitro overexpression of RSK4 induced cell arrest and senescence features in normal fibroblasts and malignant colon carcinoma cell lines. Interestingly, in these cell lines RSK4 mRNA levels were increased both in replicative and stress-induced senescence. Moreover, IMR90 partially immortalized by RSK4 shRNA and HCT116 with this short hairpin RNA were more resistant to cisplatin treatment. Finally, cells expressing E1A or Rb short interfering RNA were resistant to RSK4-mediated senescence.Conclusion: These results support the concept that RSK4 may be an important tumor suppressor gene by modulating senescence induction and contributing to cell proliferation control in colon carcinogenesis and renal cell carcinomas.