A myogenic differentiation checkpoint activated by genotoxic stress
A myogenic differentiation checkpoint activated by genotoxic stress
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DOI：
10.1038/ng1023
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发表时间：
2002-12-01
期刊：
影响因子：
30.8
通讯作者：
Wang, JYJ
中科院分区：
文献类型：
--
作者：
Puri, PL;Bhakta, K;Wang, JYJ
细胞周期检查点有助于在基因毒性应激下保护增殖细胞的基因组。在多细胞生物体中，细胞增殖通常是在发育过程中和整个成体动态平衡过程中引导分化的。为了防止具有遗传不稳定性的分化细胞的形成，我们假设遗传毒性应激可能触发分化检查点。在这里，我们表明，暴露于遗传毒性物质会导致可逆的肌源性分化抑制。如果在分化诱导之前使用DNA损伤剂，而不是在分化程序建立之后，肌肉特异性基因的表达会被DNA损伤剂抑制。成肌决定因子MyoD(由Myod1编码)是成肌细胞分化检查点的靶点。DNA损伤对MyoD的抑制需要一个功能性的c-Abl酪氨酸激酶(由ABL1编码)，但发生在缺乏p53(转化相关蛋白53，由Trp53编码)或c-jun(由癌基因jun编码)的细胞中。这些结果支持了遗传毒性应激可以调节分化的观点，并为DNA损伤激活的信号网络确定了一个新的生物学功能。
Cell-cycle checkpoints help to protect the genomes of proliferating cells under genotoxic stress. In multicellular organisms, cell proliferation is often directed toward differentiation during development and throughout adult homeostasis. To prevent the formation of differentiated cells with genetic instability, we hypothesized that genotoxic stress may trigger a differentiation checkpoint. Here we show that exposure to genotoxic agents causes a reversible inhibition of myogenic differentiation. Muscle-specific gene expression is suppressed by DNA-damaging agents if applied prior to differentiation induction but not after the differentiation program is established. The myogenic determination factor, MyoD (encoded by Myod1), is a target of the differentiation checkpoint in myoblasts. The inhibition of MyoD by DNA damage requires a functional c-Abl tyrosine kinase (encoded by Abl1), but occurs in cells deficient for p53 (transformation-related protein 53, encoded by Trp53) or c-Jun (encoded by the oncogene Jun). These results support the idea that genotoxic stress can regulate differentiation, and identify a new biological function for DNA damage-activated signaling network.