ATR and GADD45α mediate HIV-1 Vpr-induced apoptosis
ATR and GADD45α mediate HIV-1 Vpr-induced apoptosis
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DOI：
10.1038/sj.cdd.4401565
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发表时间：
2005-04-01
影响因子：
12.4
通讯作者：
Planelles, V
中科院分区：
文献类型：
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作者：
Andersen, JL;Zimmerman, ES;Planelles, V
人类免疫缺陷病毒1型（HIV-1）辅助基因vpr编码一个保守的96个氨基酸的蛋白质，是HIV-1诱导的细胞增殖阻滞所必需和足够的。vpr在CD 4+淋巴细胞中的表达导致G（2）阻滞，随后是凋亡。在以前的研究中，我们确定了共济失调毛细血管扩张突变（ATM）和Rad 3相关蛋白（ATR）作为介导Vpr诱导的细胞周期阻滞的细胞因子。在本研究中，我们报告说，乳腺癌相关蛋白-1（BRCA 1），ATR的一个已知的目标，在Vpr的存在下被激活。此外，基因编码的生长停滞和DNA损伤-45蛋白α（GADD 45 α），一个已知的BRCA 1的转录靶，上调Vpr在ATR依赖性的方式。我们证明，RNAi介导的ATR或GADD 45 a沉默导致Vpr的促凋亡作用几乎完全抑制。我们的研究结果支持一种模型，其中Vpr诱导的细胞凋亡是通过ATR磷酸化BRCA 1介导的，随后上调GADD 45 α。
The human immunodeficiency virus type-1 (HIV-1) accessory gene vpr encodes a conserved 96-amino-acid protein that is necessary and sufficient for the HIV-1-induced block of cellular proliferation. Expression of vpr in CD4+ lymphocytes results in G(2) arrest, followed by apoptosis. In a previous study, we identified the ataxia telangiectasia-mutated (ATM) and Rad3-related protein (ATR) as a cellular factor that mediates Vpr-induced cell cycle arrest. In the present study, we report that the breast cancer-associated protein-1 (BRCA1), a known target of ATR, is activated in the presence of Vpr. In addition, the gene encoding the growth arrest and DNA damage-45 protein alpha ( GADD45 alpha), a known transcriptional target of BRCA1, is upregulated by Vpr in an ATR-dependent manner. We demonstrate that RNAi-mediated silencing of either ATR or GADD45a leads to nearly complete suppression of the proapoptotic effect of Vpr. Our results support a model in which Vpr-induced apoptosis is mediated via ATR phosphorylation of BRCA1, and consequent upregulation of GADD45 alpha.