Activation of Egr-1 expression in astrocytes by HIV-1 Tat: new insights into astrocyte-mediated Tat neurotoxicity.
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.
Fan
Yan
Y
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Zou
Wei
W
Green
Linden A
LA
Kim
Byung Oh
BO
He
Johnny J
JJ
D000818:Animals; D001253:Astrocytes / Q000473:pathology / Q000821:virology*; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D051766:Early Growth Response Protein 1 / Q000096:biosynthesis* / Q000235:genetics; D015870:Gene Expression; D015658:HIV Infections / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015533:Transcriptional Activation / Q000235:genetics*; D014162:Transfection; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D054322:tat Gene Products, Human Immunodeficiency Virus