The tumor suppressor ING1 contributes to epigenetic control of cellular senescence
The tumor suppressor ING1 contributes to epigenetic control of cellular senescence
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DOI：
10.1111/j.1474-9726.2010.00651.x
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发表时间：
2011-02-01
期刊：
影响因子：
7.8
通讯作者：
Palmero, Ignacio
中科院分区：
文献类型：
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作者：
Abad, Maria;Moreno, Alberto;Palmero, Ignacio
细胞衰老是一种有效的肿瘤抑制机制，它能使具有潜在致癌性改变的细胞稳定地停止增殖。在这里，我们研究了p33ING1肿瘤抑制因子在人原代成纤维细胞衰老调控中的作用。我们发现p33ING1以p53依赖的方式触发衰老表型。此外，内源性p33ING1蛋白在癌基因衰老成纤维细胞的染色质中积累，并且其通过RNA干扰的沉默损害由癌基因触发的衰老。值得注意的是，诱导衰老的能力在人类肿瘤中存在的p33ING1突变体中丧失。使用特定的点突变体，我们进一步表明，识别的染色质标记H3K4me3是必不可少的诱导衰老的p33ING1。最后，我们证明了ING1诱导的衰老与一个特定的基因签名相关，该基因签名具有趋化因子和细胞因子信号传导因子的强代表性，该基因签名与癌基因诱导的衰老显著重叠。总之，我们的研究结果确定ING1作为人类成纤维细胞细胞衰老的关键表观遗传调节因子，并强调了其在肿瘤保护反应背景下控制基因表达的作用。
P>Cellular senescence is an effective tumor-suppressive mechanism that causes a stable proliferative arrest in cells with potentially oncogenic alterations. Here, we have investigated the role of the p33ING1 tumor suppressor in the regulation of cellular senescence in human primary fibroblasts. We show that p33ING1 triggers a senescent phenotype in a p53-dependent fashion. Also, endogenous p33ING1 protein accumulates in chromatin in oncogene-senescent fibroblasts and its silencing by RNA interference impairs senescence triggered by oncogenes. Notably, the ability to induce senescence is lost in a mutant version of p33ING1 present in human tumors. Using specific point mutants, we further show that recognition of the chromatin mark H3K4me3 is essential for induction of senescence by p33ING1. Finally, we demonstrate that ING1-induced senescence is associated to a specific genetic signature with a strong representation of chemokine and cytokine signaling factors, which significantly overlaps with that of oncogene-induced senescence. In summary, our results identify ING1 as a critical epigenetic regulator of cellular senescence in human fibroblasts and highlight its role in control of gene expression in the context of this tumor-protective response.