title: p53 transactivation of the HIV-1 long terminal repeat is blocked by PD 144795, a calcineurin-inhibitor with anti-HIV properties.
abstract: Previous reports have indicated that benzothiophenes exhibit broad anti-inflammatory properties and inhibit human immunodeficiency virus-type 1 (HIV-1) replication. We show that the immunosuppressant cyclosporin A (CsA) and benzothiophene-2-carboxamide, 5-methoxy-3-(1-methyl ethoxy)-1-oxide (PD 144795) block the induction of p53 and NF-kappaB binding to the HIV-1 long terminal repeat (LTR) by the T cell receptor activator phytohemagglutinin. CsA and PD 144795 also inhibit the induction by phytohemagglutinin of the transcription mediated by an HIV-1 LTR fragment containing the p53 and NF-kappaB sites. These effects of PD 144795 on HIV-1 transcription correlate with its ability to inhibit the phosphatase activity of calcineurin and are similar to those previously described for CsA. Moreover, a constitutive active form of calcineurin is able to induce expression from the HIV-1 LTR in a p53- and NF-kappaB-dependent manner and PD 144795 is able to block this induction. These results demonstrate that the DNA binding of p53 to the HIV-1 LTR can be modulated by calcineurin and provide a framework to understand the anti-HIV properties of benzothiophene derivatives.
authors.affiliation: Department of Physiology and Biophysics and Ireland Cancer Center, CWRU School of Medicine, Cleveland, Ohio 44106, USA. axg29@po.cwru.edu
authors.forename: A
authors.initials: A
authors.lastname: Gualberto
authors.forename: G
authors.initials: G
authors.lastname: Marquez
authors.forename: M
authors.initials: M
authors.lastname: Carballo
authors.forename: G L
authors.initials: GL
authors.lastname: Youngblood
authors.forename: S W
authors.initials: SW
authors.lastname: Hunt
authors.forename: A S
authors.initials: AS
authors.lastname: Baldwin
authors.forename: F
authors.initials: F
authors.lastname: Sobrino
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D065095:Calcineurin Inhibitors; D016325:HIV Long Terminal Repeat; D006801:Humans; D019169:Jurkat Cells; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D013876:Thiophenes / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D019380:Anti-HIV Agents; D065095:Calcineurin Inhibitors; D016328:NF-kappa B; D013876:Thiophenes; D016159:Tumor Suppressor Protein p53; C095579:PD 144795