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      p300 Modulates HIV-1 gp120-Induced Apoptosis in Human Proximal Tubular Cells: Associated with Alteration of TGF-β and Smad Signaling

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          Abstract

          p300 is a key protein, which determines acceleration or deceleration of signal transduction. Recently, renal proximal tubular cells have not only been found to be a harboring site for HIV-1 but have also been shown to undergo apoptosis in response to HIV-1 exposure. Both HIV-1 and its envelop glycoprotein, i.e. gp120, triggered tubular cell apoptosis in the same magnitude. In the present study, we evaluated the role of p300 in gp120-induced tubular cell apoptosis and associated downstream signaling. We have demonstrated that by transient transfection assays, p300 significantly increases susceptibility of human proximal renal tubular HK-2 cells to apoptosis triggered by HIV-1 gp120. A mutant p300, missing the E1A/TFIIB binding site, fails to produce such sensitization potential. Smad7 and an anti-TGF-β antibody rescue the p300 sensitization. Furthermore, p300 and HIV-1 gp120 synergistically increase TGF-β, ATF-2 and activating protein-1 (AP-1) expression. In addition, HIV-1 gp120 results in phosphorylation of Smad2 and decreases c-Jun. These findings suggest that p300 acts as a potent transcriptional cofactor in HIV-1 gp120-induced apoptosis via TGF-β and Smad signaling.

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          Most cited references 34

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          TGF-beta signal transduction.

           J Massagué (1997)
          The transforming growth factor beta (TGF-beta) family of growth factors control the development and homeostasis of most tissues in metazoan organisms. Work over the past few years has led to the elucidation of a TGF-beta signal transduction network. This network involves receptor serine/threonine kinases at the cell surface and their substrates, the SMAD proteins, which move into the nucleus, where they activate target gene transcription in association with DNA-binding partners. Distinct repertoires of receptors, SMAD proteins, and DNA-binding partners seemingly underlie, in a cell-specific manner, the multifunctional nature of TGF-beta and related factors. Mutations in these pathways are the cause of various forms of human cancer and developmental disorders.
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            Direct binding of Smad3 and Smad4 to critical TGF beta-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene.

            Smad proteins play a key role in the intracellular signalling of transforming growth factor beta (TGF beta), which elicits a large variety of cellular responses. Upon TGF beta receptor activation, Smad2 and Smad3 become phosphorylated and form heteromeric complexes with Smad4. These complexes translocate to the nucleus where they control expression of target genes. However, the mechanism by which Smads mediate transcriptional regulation is largely unknown. Human plasminogen activator inhibitor-1 (PAI-1) is a gene that is potently induced by TGF beta. Here we report the identification of Smad3/Smad4 binding sequences, termed CAGA boxes, within the promoter of the human PAI-1 gene. The CAGA boxes confer TGF beta and activin, but not bone morphogenetic protein (BMP) stimulation to a heterologous promoter reporter construct. Importantly, mutation of the three CAGA boxes present in the PAI-1 promoter was found to abolish TGF beta responsiveness. Thus, CAGA elements are essential and sufficient for the induction by TGF beta. In addition, TGFbeta induces the binding of a Smad3/Smad4-containing nuclear complex to CAGA boxes. Furthermore, bacterially expressed Smad3 and Smad4 proteins, but not Smad1 nor Smad2 protein, bind directly to this sequence in vitro. The presence of this box in TGF beta-responsive regions of several other genes suggests that this may be a widely used motif in TGF beta-regulated transcription.
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              Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling.

              TGF-beta signals from the membrane to the nucleus through serine/threonine kinase receptors and their downstream effectors, termed SMAD proteins. The activated TGF-beta receptor induces phosphorylation of two such proteins, Smad2 and Smad3, which form hetero-oligomeric complex(es) with Smad4/DPC4 that translocate to the nucleus, where they then regulate transcriptional responses. However, the mechanisms by which the intracellular signals of TGF-beta are switched off are unclear. Here we report the identification of Smad7, which is related to Smad6. Transfection of Smad7 blocks responses mediated by TGF-beta in mammalian cells, and injection of Smad7 RNA into Xenopus embryos blocks activin/TGF-beta signalling. Smad7 associates stably with the TGF-beta receptor complex, but is not phosphorylated upon TGF-beta stimulation. TGFbeta-mediated phosphorylation of Smad2 and Smad3 is inhibited by Smad7, indicating that the antagonistic effect of Smad7 is exerted at this important regulatory step. TGF-beta rapidly induces expression of Smad7 mRNA, suggesting that Smad7 may participate in a negative feedback loop to control TGF-beta responses.
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                Author and article information

                Journal
                NEE
                Nephron Exp Nephrol
                10.1159/issn.1660-2129
                Cardiorenal Medicine
                S. Karger AG
                1660-2129
                2006
                January 2006
                22 September 2005
                : 102
                : 1
                : e30-e38
                Affiliations
                aDivision of Nephrology, Department of Medicine, and bDepartment of Radiation Oncology, Long Island Jewish Medical Center, The Long Island Campus for Albert Einstein College of Medicine, New Hyde Park, N.Y., USA
                Article
                88404 Nephron Exp Nephrol 2006;102:e30–e38
                10.1159/000088404
                16179804
                © 2006 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 5, References: 50, Pages: 1
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/88404
                Categories
                Original Paper

                Cardiovascular Medicine, Nephrology

                p300, Apoptosis, Smads, gp120, Transforming growth factor-β, AP-1, HIV-1

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