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J. Biol. Chem., Vol. 282, Issue 7, 4288-4300, February 16, 2007

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Activation of JNK-dependent Pathway Is Required for HIV Viral Protein R-induced Apoptosis in Human Monocytic Cells

INVOLVEMENT OF ANTIAPOPTOTIC BCL2 AND c-IAP1 GENES^*

Sasmita Mishra¹, Jyoti P. Mishra¹, and Ashok Kumar^¶2

From the Departments of Pathology and Laboratory Medicine and Biochemistry, Microbiology, and Immunology, University of Ottawa K1H 8M5 and ^¶Infectious Disease and Vaccine Research Centre, Research Institute, Children’s Hospital of Eastern Ontario, Ottawa, Ontario K1H 8L1, Canada

Human immunodeficiency virus (HIV) accessory protein viral protein R (Vpr) plays a key role in virus replication and induces cell cycle arrest and apoptosis in various cell types including T cells and neuronal and tumor cells following infection with Vpr-expressing HIV isolates or exposure to the extracellular Vpr protein. The C-terminal Vpr peptide encompassing amino acids 52–96 (Vpr-(52–96)) is required for exerting the apoptotic effects, whereas the N-terminal Vpr-(1–45) peptide is responsible for virus transcription. We demonstrate that Vpr-(52–96) induced apoptosis in human promonocytic THP-1 cells and primary monocytes through the mitochondrial pathway in a caspase-dependent manner. To understand the regulation of Vpr-induced apoptosis, we investigated the signaling pathways, particularly the MAPKs, and the transcription factors involved. Although both Vpr-(52–96) and Vpr-(1–45) peptides induced phosphorylation of all the three members of the MAPKs, Vpr-(52–96)-activated JNK selectively induced apoptosis in monocytic cells through the mitochondrial pathway as determined by using JNK inhibitors SP60025, dexamethasone, curcumin, and JNK-specific small interfering RNAs. Furthermore Vpr-(52–96)-induced apoptosis was mediated by inhibition of downstream antiapoptotic Bcl2 and c-IAP1 genes whose expression could be restored following pretreatment with JNK-specific inhibitors. Overall the results suggest that Vpr-(52–96)-activated JNK plays a key role in inducing apoptosis through the down-regulation of antiapoptotic Bcl2 and c-IAP1 genes.

Received for publication, August 30, 2006 , and in revised form, November 27, 2006.

^* This work was supported in part by grants from the Canadian Institutes of Health Research (to A. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by the Ontario Graduate Scholarship in Science and Technology and Ontario Graduate Scholarship.

² Recipient of the Career Scientist Award from the Ontario HIV Treatment Network. To whom correspondence should be addressed: Division of Virology, Research Inst., Children’s Hospital of Eastern Ontario, University of Ottawa, 401 Smyth Rd., Ottawa, Ontario K1H 8L1, Canada. Tel.: 613-737-7600 (ext. 3920); Fax: 613-738-4825; E-mail: akumar{at}uottawa.ca.

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