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      Infection of Human Immunodeficiency Virus and Intracellular Viral Tat Protein Exert a Pro-survival Effect in a Human Microglial Cell Line


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          The interaction of human immunodeficiency virus type 1 (HIV-1) with CD4+ T lymphocytes is well studied and typically results in virally induced cytolysis. In contrast, relatively little is known concerning the interplay between HIV-1 and microglia. Recent findings suggest that, counter-intuitively, HIV-1 infection may extend the lifespan of microglia. We developed a novel cell line model system to confirm and mechanistically study this phenomenon. We found that transduction of a human microglial cell line with an HIV-1 vector results in a powerful cytoprotective effect following apoptotic challenge. This effect was reproduced by ectopic expression of a single virus-encoded protein, Tat. Subsequent studies showed that the pro-survival effects of intracellular Tat could be attributed to activation of the PI-3-kinase (PI3K)/Akt pathway in the microglial cell line. Furthermore, we found that expression of Tat led to decreased expression of PTEN, a negative regulator of the PI-3-K pathway. Consistent with this, decreased p53 activity and increased E2F activity were observed. Based on these findings, a model of possible regulatory circuits that intracellular Tat and HIV-1 infection engage during the cytoprotective event in microglia has been suggested. We propose that the expression of Tat may enable HIV-1 infected microglia to survive throughout the course of infection, leading to persistent HIV-1 production and infection in the central nervous system.

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          PI3K/Akt and apoptosis: size matters.

          Recent research has examined Akt and Akt-related serine-threonine kinases in signaling cascades that regulate cell survival and are important in the pathogenesis of degenerative diseases and in cancer. We seek to recapitulate the research that has helped to define the current understanding of the role of the Akt pathway under normal and pathologic conditions, also in view of genetic models of Akt function. In particular, we will evaluate the mechanisms of Akt regulation and the role of Akt substrates in Akt-dependent biologic responses in the decisions of cell death and cell survival. Here, we hope to establish the mechanisms of apoptosis suppression by Akt kinase as a framework for a more general understanding of growth factor-dependent regulation of cell survival.
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            The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase.

            The serine/threonine protein kinase encoded by the Akt proto-oncogene is catalytically inactive in serum-starved primary and immortalized fibroblasts. Here we show that Akt and the Akt-related kinase AKT2 are activated by PDGF. The activation was rapid and specific, and it was abrogated by mutations in the Akt Pleckstrin homology (PH) domain. The Akt activation was also shown to depend on PDGFR beta tyrosines Y740 and Y751, which bind phosphatidylinositol 3-kinase (PI 3-kinase) upon phosphorylation. Moreover, Akt activation was blocked by the PI 3-kinase-specific inhibitor wortmannin and the dominant inhibitory N17Ras. Conversely, Akt activity was induced following the addition of phosphatidylinositol-3-phosphate to Akt immunoprecipitates from serum-starved cells in vitro. These results identify Akt as a novel target of PI 3-kinase and suggest that the Akt PH domain may be a mediator of PI 3-kinase signaling.
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              Cytoplasmic localization of p21Cip1/WAF1 by Akt-induced phosphorylation in HER-2/neu-overexpressing cells.

              Amplification or overexpression of HER-2/neu in cancer cells confers resistance to apoptosis and promotes cell growth. The cellular localization of p21Cip1/WAF1 has been proposed to be critical either in promoting cell survival or in inhibiting cell growth. Here we show that HER-2/neu-mediated cell growth requires the activation of Akt, which associates with p21Cip1/WAF1 and phosphorylates it at threonine 145, resulting in cytoplasmic localization of p21Cip1/WAF1. Furthermore, blocking the Akt pathway with a dominant-negative Akt mutant restores the nuclear localization and cell-growth-inhibiting activity of p21Cip1/WAF1. Our results indicate that HER-2/neu induces cytoplasmic localization of p21Cip1/WAF1 through activation of Akt to promote cell growth, which may have implications for the oncogenic activity of HER-2/neu and Akt.

                Author and article information

                J Mol Biol
                J. Mol. Biol
                Journal of Molecular Biology
                Published by Elsevier Ltd.
                10 November 2006
                9 February 2007
                10 November 2006
                : 366
                : 1
                : 67-81
                [1 ]Department of Microbiology and Immunology, School of Medicine, University of Rochester Medical Center, 601 Elmwood Avenue, Box 672, Rochester, NY 14742, USA
                [2 ]Division of Cellular Biology and Immunology, Department of Pathology, University of Utah School of Medicine, 30 N 1900 East, SOM 5C210, Salt Lake City, UT 84132, USA
                Author notes
                [* ]Corresponding author. baek_kim@ 123456urmc.rochester.edu
                Copyright © 2006 Published by Elsevier Ltd.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                : 16 September 2006
                : 31 October 2006
                : 2 November 2006

                Molecular biology
                hiv-1, human immunodeficiency virus type 1,pten, phosphatase and tensin homolog,cns, central nervous system,hcv, hepatitis type c virus,htlv-1, human t-cell leukemia virus type 1,pi-3-k, pi-3-kinase,chx, cycloheximide,gfp, green fluorescent protein,cmv, cytomegalovirus,lps, lipopolysaccharide,snp, sodium nitroprusside,moi, multiplicity of infection,pbmc, peripheral blood mononuclear cells,hiv-1,microglia,viral reservoir,tat,long-term survival


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