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Adenovirus encoding HIV-1 Vpr activates caspase 9 and induces apoptotic cell death in both p53 positive and negative human tumor cell lines

Oncogene volume 21, pages 4613–4625 (2002)Cite this article

Abstract

The targeted delivery of genes whose products arrest the cell cycle and/or induce apoptosis represent an important tool for the understanding and controlling forms of unregulated cell growth. The vpr gene product of HIV-1 has been reported to interfere with cell growth and induce apoptosis, but the mechanism of its action is not clearly understood. In order to study these important properties of Vpr, we created a recombinant adenovirus H5.010CMV-vpr (adCMV-vpr) as a tool to deliver the vpr gene to various cell lines to examine its biology. Vpr protein expression was confirmed by Western blot analysis in adCMV-vpr infected cells. We tested the effects of adCMV-vpr on cell growth of several tumor cell lines. Infection of both p53 positive and p53 deficient tumor cell lines with adCMV-vpr resulted in dramatic induction of cell death in short-term assays. We observed that apoptosis was induced through the mitochondrial pathway as we observed changes in the cytochrome c content accompanied by caspase 9 activation. As Bcl-2 is reported to interfere with apoptosis through the mitochondrial pathway, we examined the effect of adCMV-vpr in Bcl-2 over expressing cell lines. We observed that Bcl-2 overexpression does not inhibit adCMV-vpr induced apoptosis. The properties of adCMV-vpr inducing apoptosis through caspase 9 in a p53 pathway independent manner suggest that this is an important reagent. Such a vector may give insight into approaches designed to limit the growth of pathogenic human cells.

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Acknowledgements

This work was supported in parts by Seed project grants from the Institute of Human Gene Therapy, UPENN and NIH grants to DB Weiner.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, PA, USA

    Karuppiah Muthumani, Donghui Zhang, Daniel S Hwang, Sagar Kudchodkar, Nathanael S Dayes, Afshan S Malik, Joo-Sung Yang, Michael A Chattergoon, Henry C Maguire Jr & David B Weiner

  2. Viral Genomix, 3600 Market Street, Suite 100, Philadelphia, 19104, Pennsylvania, PA, USA

    Brijal M Desai

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  1. Karuppiah Muthumani
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  2. Donghui Zhang
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Correspondence to David B Weiner.

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Muthumani, K., Zhang, D., Hwang, D. et al. Adenovirus encoding HIV-1 Vpr activates caspase 9 and induces apoptotic cell death in both p53 positive and negative human tumor cell lines. Oncogene 21, 4613–4625 (2002). https://doi.org/10.1038/sj.onc.1205549

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