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ATR and GADD45alpha mediate HIV-1 Vpr-induced apoptosis
J L Andersen1, E S Zimmerman, J L DeHart
1Department of Pathology, Division of Cellular Biology and Immunology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
Cell Death and Differentiation
|January 15, 2005
Summary
The HIV-1 Vpr protein induces cell cycle arrest and apoptosis. This study shows Vpr triggers apoptosis via ATR-mediated BRCA1 activation and GADD45alpha upregulation.
Area of Science:
- Virology
- Cell Biology
- Molecular Biology
Background:
- The human immunodeficiency virus type-1 (HIV-1) accessory gene vpr encodes a protein crucial for viral replication.
- Vpr is known to induce cell cycle arrest and apoptosis in host cells, particularly CD4+ lymphocytes.
- The ataxia telangiectasia-mutated (ATM) and Rad3-related protein (ATR) has been identified as a mediator of Vpr-induced cell cycle arrest.
Purpose of the Study:
- To elucidate the molecular mechanisms by which Vpr induces apoptosis.
- To investigate the role of breast cancer-associated protein-1 (BRCA1) and growth arrest and DNA damage-45 protein alpha (GADD45alpha) in Vpr-mediated apoptosis.
Main Methods:
- Investigated the activation of BRCA1 in the presence of Vpr.
- Assessed the upregulation of GADD45alpha by Vpr in an ATR-dependent manner.
- Utilized RNA interference (RNAi) to silence ATR or GADD45alpha and evaluate the suppression of Vpr's proapoptotic effect.
Main Results:
- Vpr activates BRCA1, a known target of ATR.
- Vpr upregulates GADD45alpha, a transcriptional target of BRCA1, in an ATR-dependent manner.
- Silencing of ATR or GADD45alpha significantly suppresses Vpr-induced apoptosis.
Conclusions:
- Vpr-induced apoptosis is mediated by a pathway involving ATR.
- ATR phosphorylates BRCA1, leading to its activation.
- Activated BRCA1 subsequently upregulates GADD45alpha, contributing to apoptosis.