Myc suppresses induction of the growth arrest genes gadd34, gadd45, and gadd153 by DNA-damaging agents
Myc suppresses induction of the growth arrest genes gadd34, gadd45, and gadd153 by DNA-damaging agents
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DOI：
10.1038/sj.onc.1202136
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发表时间：
1998-10-29
期刊：
影响因子：
8
通讯作者：
Fornace, AJ
中科院分区：
文献类型：
--
作者：
Amundson, SA;Zhan, Q;Fornace, AJ
生长停滞和DNA损伤诱导（gadd）基因诱导的各种遗传毒性和非遗传毒性的压力，如血清饥饿，紫外线照射和烷化剂处理。它们的协同诱导是一种生长停滞信号，可能在细胞对DNA损伤的反应中起重要作用。相反，c-myc是一种强的增殖信号，并且Myc的过表达经常在癌细胞中观察到。我们已经发现，V-myc在RAT-1细胞中的异位表达导致甲磺酸甲酯（MMS）对三种主要gadd转录物的减弱诱导，并且几乎完全阻断对紫外线（UV）辐射的响应。Myc的作用部分是通过降低gadd 45启动子的应激反应，因为c-myc表达载体强烈抑制了gadd-reporter构建体的激活。Myc的这种活性定位于gadd 45启动子内最近描述的富含CC的结合位点。这些结果表明，协调下调gadd基因的反应是一种机制，Myc可以绕过生长停滞，并有助于肿瘤表型。
The growth arrest and DNA damage inducible (gadd) genes are induced by various genotoxic and nongenotoxic stresses such as serum starvation, ultraviolet irradiation and treatment with alkylating agents. Their coordinate induction is a growth arrest signal which may play an important role in the response of cells to DNA damage. Conversely, c-myc is a strong proliferative signal, and overexpression of Myc is frequently observed in cancer cells, We have found that ectopic expression of v-myc in RAT-I cells results in an attenuated induction of the three major gadd transcripts by methyl methanesulfonate (MMS), and almost completely blocks the response to ultraviolet (UV) radiation. Myc acts in part by reducing the stress-responsiveness of the gadd45 promoter, as a c-myc expression vector strongly suppressed activation of gadd-reporter constructs. This activity of Myc localizes to a recently described CC-rich binding site within the gadd45 promoter. These results indicate that a coordinate down-regulation of the gadd gene response is one mechanism by which Myc can circumvent growth arrest and contribute to the neoplastic phenotype.