ATM-dependent expression of IEX-1 controls nuclear accumulation of Mcl-1 and the DNA damage response.
ATM-dependent expression of IEX-1 controls nuclear accumulation of Mcl-1 and the DNA damage response.
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DOI：
10.1038/cdd.2010.56
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发表时间：
2010-11
影响因子：
12.4
通讯作者：
中科院分区：
文献类型：
--
作者：
早期反应基因产物IEX-1(也称为IER3)最近被发现与抗凋亡的Bcl-2家族成员髓系细胞白血病-1(Mcl-1)相互作用。在这项研究中，我们证明了这种相互作用特异性地和及时地控制了Mcl-1在细胞核中的积累，以响应DNA损伤。IEX-1蛋白被γ辐射、基因毒性药物或复制抑制剂快速诱导，依赖于共济失调毛细血管扩张突变(ATM)活性，是McL-1核转位所必需的。相反，IEX-1蛋白的蛋白酶体降解触发Mcl-1返回胞浆。IEX-1和McL-1是DNA损伤反应的重要组成部分。IEX-1或Mcl-1的缺失会导致基因组不稳定，并增加对遗传毒性和复制应激的敏感性。这两个蛋白质协同维持Chk1的激活和G2检查点的停滞。MCL-1核转位可能会形成检查点，提高肿瘤对DNA损伤为基础的癌症治疗的抵抗力。破译IEX-1降解的途径应该会导致发现新的治疗靶点，以提高肿瘤细胞对化疗的敏感性。
The early-response gene product IEX-1 (also known as IER3) was recently found to interact with the anti-apoptotic Bcl-2 family member, myeloid cell leukemia-1 (Mcl-1). In this study we show that this interaction specifically and timely controls the accumulation of Mcl-1 in the nucleus in response to DNA damage. The IEX-1 protein is rapidly induced by γ-irradiation, genotoxic agents or replication inhibitors, in a way dependent on ataxia telangiectasia mutated (ATM) activity and is necessary for Mcl-1 nuclear translocation. Conversely, IEX-1 protein proteasomal degradation triggers the return of Mcl-1 to the cytosol. IEX-1 and Mcl-1 are integral components of the DNA damage response. Loss of IEX-1 or Mcl-1 leads to genomic instability and increased sensitivity to genotoxic and replicative stresses. The two proteins cooperate to maintain Chk1 activation and G2 checkpoint arrest. Mcl-1 nuclear translocation may foster checkpoint and improve the tumor resistance to DNA damage-based cancer therapies. Deciphering the pathways involved in IEX-1 degradation should lead to the discovery of new therapeutic targets to increase sensitivity of tumor cells to chemotherapy.
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影响因子：
56.9
作者：
Opferman, JT;Iwasaki, H;Korsmeyer, SJ
通讯作者：
Korsmeyer, SJ
影响因子：
3.3
作者：
Sommer, SL;Berndt, TJ;Kumar, R
通讯作者：
Kumar, R
影响因子：
20.3
作者：
Hamelin, V;Letourneux, C;Gaudry, M
通讯作者：
Gaudry, M
影响因子：
64.5
作者：
Kamer, I;Sarig, R;Gross, A
通讯作者：
Gross, A
影响因子：
11.4
作者：
Letourneux, C;Rocher, G;Porteu, F
通讯作者：
Porteu, F