Human immunodeficiency virus type 1 (HIV-1) Tat protein is a major pathogenic
factor in HIV-associated neurological diseases; it exhibits direct neurotoxicity and indirect
astrocyte-mediated neurotoxicity. We have shown that Tat alone is capable of activating glial
fibrillary acidic protein (GFAP) expression and inducing astrocytosis involving sequential
activation of early growth response protein 1 (Egr-1) and p300. In this study, we determined the
roles of signal transducer and activator of transcription 3 (STAT3) in Tat-induced GFAP
transactivation. STAT3 expression and phosphorylation led to significant increases in GFAP
transcription and protein expression. Tat expression was associated with increased STAT3
expression and phosphorylation in Tat-expressing astrocytes and HIV-infected astrocytes.
GFAP, Egr-1 and p300 transcription and protein expression all showed positive response to
STAT3 and its phosphorylation. Importantly, knockdown of STAT3 resulted in significant
decreases in Tat-induced GFAP and Egr-1 transcription and protein expression. Taken together,
these findings show that STAT3 is involved in and acts upstream of Egr1 and p300 in the Tat-induced GFAP
transactivation cascade and suggest important roles of STAT3 in controlling astrocyte proliferation and activation in the
HIV-infected central nervous system.
Keywords: Astrocytes, HIV-1 Tat, Egr-1, p300, GFAP, STAT3.
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