Abstract
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 G2 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 α (GADD45α), 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 GADD45α 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 GADD45α.
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Abbreviations
- GADD45α:
-
growth arrest and DNA damage-45 alpha
- Vpr:
-
viral protein R
- BRCA1:
-
breast cancer-associated-1 gene
- ATM:
-
ataxia telangiectasia-mutated
- ATR:
-
ATM- and Rad3-related
- CHK2:
-
checkpoint kinase-2
- HIV-1:
-
human immunodeficiency virus type-1
- PTPC:
-
permeability transition pore complex
- PLK1:
-
polo-like kinase-1
- CHK1:
-
checkpoint kinase-1
- H2AX:
-
histone 2A variant-X
- 53BP1:
-
p53-binding protein-1
- JNK/SAPK:
-
c-jun N-terminal kinase/stress-activated protein kinase
- PARP:
-
poly(ADP-ribose) polymerase
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Acknowledgements
We thank Dr. Wayne Green, Todd Kinard, and Michael Blackwell for excellent technical help. We are grateful to Dr. Paul Nghiem for providing antibodies to ATR. This work was supported by an NIH research grant to VP (R01AI49057).
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Andersen, J., Zimmerman, E., DeHart, J. et al. ATR and GADD45α mediate HIV-1 Vpr-induced apoptosis. Cell Death Differ 12, 326–334 (2005). https://doi.org/10.1038/sj.cdd.4401565
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DOI: https://doi.org/10.1038/sj.cdd.4401565
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