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Abstract
Apoptosis in HIV-1-infected CD4+ primary T cells is triggered by the alteration of the PI3K and p53 pathways, which converge on the FOXO3a transcriptional activator. Tat alone can cause activation of FOXO3a and of its proapoptotic target genes. To understand how Tat affects this pathway, we carried out ChIP-Chip experiments with Tat. Tat associates with the promoters of PTEN and two PP2A subunit genes, but not with the FOXO3a promoter. PTEN and PP2A encode phosphatases, whose levels and activity are increased when Tat is expressed. They counteract phosphorylation of Akt1 and FOXO3a, and so activate transcriptional activity of FOXO3a. FOXO3a promotes increased transcription of Egr-1, which can further stimulate the transcription of PTEN, thereby reinforcing the pathway that leads to FOXO3a transcriptional activation. RNAi experiments support the role of PTEN and PP2A in the initiation of the Tat-mediated cascade, which is critical to apoptosis. The increased accumulation of PTEN and PP2A subunit mRNAs during Tat expression is more likely to be the result of increased transcription initiation and not relief of promoter-proximal pausing of RNAPII. The Tat-PTEN and -PP2A promoter interactions provide a mechanistic explanation of Tat-mediated apoptosis in CD4+ T cells.
Highlights
HIV-1-infected CD4+ primary T cells progress to the G0 phase of the cell cycle and to cell death [1]
To gain insight into the molecular mechanism by which Tat protein affects the phosphatase and tensin homolog (PTEN)-FOXO3a-Early Growth Response Protein 1 (Egr-1) signaling pathway, we investigated the impact of the HIV-1 Tat protein on the regulation of FOXO3a in Jurkat T cells
We investigated whether Tat expression in Jurkat cells resulted in modulatory effects on expression of proapoptotic genes, similar to those we observed in primary CD4+ T cells infected with HIVD2GFP, HIVD3GFP, and wild-type viruses [1]
Summary
HIV-1-infected CD4+ primary T cells progress to the G0 phase of the cell cycle and to cell death [1]. Apoptosis in these cells is triggered by the alteration of transcriptional pathways that converge on the Forkhead box O3 (FOXO3a) transcriptional activator. The induction of phosphatase and tensin homolog (PTEN) and FOXO3a was observed in cells that express only the Tat protein, suggesting that Tat may be a key player in the activation of these pathways. Increased expression of PTEN reduces serine/ threonine protein kinase pAkt levels, which cause reduced phosphorylation of FOXO3a. Unphosphorylated FOXO3a translocates to the nucleus and becomes transcriptionally active [7]
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