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Activation of Egr-1 Expression in Astrocytes by HIV-1 Tat: New Insights into Astrocyte-Mediated Tat Neurotoxicity

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Abstract

Human immunodeficiency virus type 1 (HIV-1) Tat plays an important role in HIV-associated neuropathogenesis; the underlying mechanisms are still evolving. We have recently shown that HIV-1 Tat induces expression of glial fibrillary acidic protein (GFAP), a characteristic of HIV-1 infection of the central nervous system. We have also shown that the Tat-induced GFAP expression in astrocytes is regulated by p300 and that deletion of the early growth response 1 (Egr-1) cis-transacting element within the p300 promoter abolishes Tat-induced GFAP expression. In this study, we further examined the relationship between Tat and Egr-1 in astrocytes. We found increased Egr-1 protein expression in Tat-expressing human astrocytoma cells and mouse primary astrocytes. Using the Egr-1 promoter-driven firefly luciferase reporter gene assay and the site-directed mutagenesis, we demonstrated that Tat increased Egr-1 expression by transactivating the Egr-1 promoter and involving specific serum response elements within the promoter. Consistent with these data, we showed that Tat transactivation of the Egr-1 promoter was abrogated when astrocytes were cultured in serum-reduced media. Taken together, these results reveal that Tat directly transactivates Egr-1 expression and suggest that Tat interaction with Egr-1 is probably one of the very upstream molecular events that initiate Tat-induced astrocyte dysfunction and subsequent Tat neurotoxicity.

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Acknowledgments

This work is supported in part by the National Institutes of Health grants R01NS039804 and R01NS065875 (to JJH).

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Authors and Affiliations

  1. Department of Microbiology and Immunology, Indiana University School of Medicine, R2 302, 950W. Walnut St., Indianapolis, IN, 46202, USA

    Yan Fan, Wei Zou, Linden A. Green & Johnny J. He

  2. Department of Applied Biology, College of Life Science and Natural Resources, Kyungpook National University, Sangju, 742-711, Republic of Korea

    Byung Oh Kim

  3. Center for AIDS Research, Indiana University School of Medicine, R2 302, 950W. Walnut St., Indianapolis, IN, 46202, USA

    Johnny J. He

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  1. Yan Fan
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  2. Wei Zou
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  3. Linden A. Green
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  5. Johnny J. He
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Correspondence to Johnny J. He.

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Part of this work was presented at the 15th Annual Conference of the Society of Neuroimmune Pharmacology in April 2008 and at the 9th International Symposium on Neurovirology in June 2009.

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Fan, Y., Zou, W., Green, L.A. et al. Activation of Egr-1 Expression in Astrocytes by HIV-1 Tat: New Insights into Astrocyte-Mediated Tat Neurotoxicity. J Neuroimmune Pharmacol 6, 121–129 (2011). https://doi.org/10.1007/s11481-010-9217-8

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