ATR and GADD45α mediate HIV-1 Vpr-induced apoptosis

被引:56
作者
Andersen, JL
Zimmerman, ES
DeHart, JL
Murala, S
Ardon, O
Blackett, J
Chen, J
Planelles, V
机构
[1] Univ Utah, Sch Med, Dept Pathol, Div Cell Biol & Immunol, Salt Lake City, UT 84132 USA
[2] Mayo Clin, Div Oncol Res, Rochester, MN 55905 USA
关键词
apoptosis; HIV; Vpr; ATR; BRCA1; GADD45;
D O I
10.1038/sj.cdd.4401565
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:326 / 334
页数:9
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