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Blood, 15 September 2005, Vol. 106, No. 6, pp. 2059-2068. Prepublished online as a Blood First Edition Paper on May 31, 2005; DOI 10.1182/blood-2005-03-0932. This Article Full Text (PDF) All Versions of this Article: 2005-03-0932v1 106/6/2059    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Muthumani, K. Articles by Weiner, D. B Search for Related Content PubMed PubMed Citation Articles by Muthumani, K. Articles by Weiner, D. B Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 9, 2005 Accepted May 19, 2005 HIV-1 Nef-induced FasL induction and bystander killing requires p38 MAPK activation Karuppiah Muthumani, Andrew Y Choo, Daniel S Hwang, Arumugam Premkumar, Nathanael S Dayes, Crafford Harris, Douglas R Green, Scott A Wadsworth, John J Siekierka, and David B Weiner* Dept of Pathology and Lab. Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA Memorial Sloan-Kettering Cancer Center, New York, NY, USA Johnson & Johnson Pharmaceutical Research & Development, Raritan, NJ, USA La Jolla Institute for Allergy and Immunology, San Diego, CA, USA * Corresponding author; email: dbweiner{at}mail.med.upenn.edu. The Human Immunodeficiency Virus (HIV) has been reported to target non-infected CD4 and CD8 cells for destruction. This effect is manifested in part through upregulation of the death receptor FasL by HIV-1 Nef leading to bystander damage. However, the signal transduction and transcriptional regulation of this process remains elusive. Here, we provide evidence supporting that p38 MAPK is required for this process. Loss of function experiments through dominant negative p38 isoform, p38 siRNA, and chemical inhibitors of p38 activation suggest that p38 is necessary for Nef-induced AP-1 activation, as inhibition leads to an attenuation of AP-1 dependent transcription. Furthermore, mutagenesis of the FasL promoter reveals that its AP-1 enhancer element is required for Nef-mediated transcriptional activation. Therefore, a linear pathway for Nef-induced FasL expression that encompasses p38 and AP-1 has been elucidated. Furthermore, chemical inhibition of the p38 pathway attenuates HIV-1 mediated bystander killing of CD8 cells in vitro. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: p38 MAP kinase in HIV-1 infection: the enemy within Jean-Luc Perfettini and Guido Kroemer Blood 2005 106: 1899-1900. [Full Text] [PDF] This article has been cited by other articles: W. Ma, S. Mishra, N. Gajanayaka, J. B. Angel, and A. Kumar HIV-1 Nef Inhibits Lipopolysaccharide-induced IL-12p40 Expression by Inhibiting JNK-activated NF{kappa}B in Human Monocytic Cells J. Biol. Chem., March 20, 2009; 284(12): 7578 - 7587. [Abstract] [Full Text] [PDF] K. Muthumani, A. Y. Choo, D. J. Shedlock, D. J. Laddy, S. G. Sundaram, L. Hirao, L. Wu, K. P. Thieu, C. W. Chung, K. M. Lankaraman, et al. Human Immunodeficiency Virus Type 1 Nef Induces Programmed Death 1 Expression through a p38 Mitogen-Activated Protein Kinase-Dependent Mechanism J. Virol., December 1, 2008; 82(23): 11536 - 11544. [Abstract] [Full Text] [PDF] D. Gutierrez-Sanmartin, E. Varela-Ledo, A. Aguilera, S. 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Vaccari, S. Manrique, G. Romeo, M. Federico, M. Geyer, and E. Affabris In Vitro Treatment of Human Monocytes/Macrophages with Myristoylated Recombinant Nef of Human Immunodeficiency Virus Type 1 Leads to the Activation of Mitogen-Activated Protein Kinases, I{kappa}B Kinases, and Interferon Regulatory Factor 3 and to the Release of Beta Interferon J. Virol., March 15, 2007; 81(6): 2777 - 2791. [Abstract] [Full Text] [PDF]

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