Kato Hiroyuki, Honma Reiko, Sanda Takaomi, Fujiwara Toshiyoshi, Ito Emi, Yanagisawa Yuka, Imai Jun-ichi, Okamoto Takashi, Watanabe Shinya
Department of Virology III, National Institute of Infectious Diseases, Musashimurayama, Tokyo, Japan.
Biochem Biophys Res Commun. 2007 Sep 28;361(3):580-5. doi: 10.1016/j.bbrc.2007.07.035. Epub 2007 Jul 25.
hSNF5/Ini1 is a core component of the SWI/SNF complex and the gene is frequently mutated in aggressive pediatric rhabdoid tumors. Mechanisms of the malignant transformation, however, remain poorly understood. We analyzed HeLa cells treated with siRNA to the hSNF5/Ini1 mRNA. The resulting efficient and long-term suppression caused characteristic cell enlargement, cell cycle arrest in G1 phase, and subsequent modest apoptosis. Gene expression profiling of the hSNF5-down-regulated cells by cDNA microarray analysis revealed that a limited number of p53-responsive genes, especially p21, were up-regulated. The p53 protein level was also greatly enhanced, suggesting that loss of hSNF5/Ini1 induces a p53 signaling pathway irrelevant to the chk1/2 phosphorylation pathway. Some rhabdoid tumors with very low or no ARF expression were induced to undergo cell enlargement, growth arrest, and, in one case, apoptosis by ectopic expression of the p14ARF protein. These results may in part account for molecular mechanisms of rhabdoid tumor formation.
hSNF5/Ini1是SWI/SNF复合物的核心成分，该基因在侵袭性儿童横纹肌肉瘤中经常发生突变。然而，恶性转化的机制仍知之甚少。我们分析了用针对hSNF5/Ini1 mRNA的小干扰RNA（siRNA）处理的HeLa细胞。由此产生的高效且长期的抑制导致细胞出现特征性增大、细胞周期停滞于G1期，并随后出现适度凋亡。通过cDNA微阵列分析对hSNF5下调细胞进行基因表达谱分析发现，有限数量的p53反应性基因，尤其是p21，被上调。p53蛋白水平也大幅增强，这表明hSNF5/Ini1的缺失诱导了一条与chk1/2磷酸化途径无关的p53信号通路。一些ARF表达极低或无表达的横纹肌肉瘤通过异位表达p14ARF蛋白而被诱导出现细胞增大、生长停滞，在一个病例中还出现了凋亡。这些结果可能部分解释了横纹肌肉瘤形成的分子机制。
