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      Role of the E2F1-p19 ARF-p53 Pathway in Ischemic Acute Renal Failure

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          Abstract

          Background: Cell cycle progression and arrest of renal tubular cells after acute injury is a reactive process of renal regeneration. The p16<sup>INK4a</sup>/p19<sup>ARF</sup> (alternative reading frame) locus encodes two proteins involved in cell cycle regulation. We investigated the transcriptional regulation and tissue distribution of p19<sup>ARF</sup> in ischemic acute renal failure (ARF). Methods: We examined the time course and immunohistochemistry of p19<sup>ARF</sup> in rat kidneys following the induction of ischemic ARF. We also examined the effect of p19<sup>ARF</sup> overexpression on p53 levels and cell cycle progression in MDCK cells. Results: The protein expression of p19<sup>ARF</sup> strongly increased 72 h after the ischemia. Immunohistochemical studies showed that the renal tubular cells in the outer medulla expressed p19<sup>ARF</sup> protein 72 h after ischemic injury. The time course of E2F1 induction was observed at 6–24 h, and it was found to precede p19<sup>ARF</sup> expression. In MDCK cells, the overexpression of E2F1 increased promoter activity and the protein level of p19<sup>ARF</sup> and induced apoptosis. Transfection of the p19<sup>ARF</sup> expression vector caused an increase in p53 protein, cell cycle arrest and apoptosis. Conclusions: These data support the hypothesis that the E2F1-p19<sup>ARF</sup>-p53 pathway forms a negative feedback loop to regulate the cell cycle of renal tubular cells in the ischemic ARF.

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          Most cited references 27

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          Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF.

          The INK4a tumor suppressor locus encodes p16INK4a, an inhibitor of cyclin D-dependent kinases, and p19ARF, an alternative reading frame protein that also blocks cell proliferation. Surprisingly, mice lacking p19ARF but expressing functional p16INK4a develop tumors early in life. Their embryo fibroblasts (MEFs) do not senesce and are transformed by oncogenic Ha-ras alone. Conversion of ARF+/+ or ARF+/- MEF strains to continuously proliferating cell lines involves loss of either p19ARF or p53. p53-mediated checkpoint control is unperturbed in ARF-null fibroblast strains, whereas p53-negative cell lines are resistant to p19ARF-induced growth arrest. Therefore, INK4a encodes growth inhibitory proteins that act upstream of the retinoblastoma protein and p53. Mutations and deletions targeting this locus in cancer cells are unlikely to be functionally equivalent.
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            ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways.

            The INK4a-ARF locus encodes two unrelated proteins that both function in tumor suppression. p16INK4 binds to and inhibits the activity of CDK4 and CDK6, and ARF arrests the cell cycle in a p53-dependent manner. We show here that ARF binds to MDM2 and promotes the rapid degradation of MDM2. This interaction is mediated by the exon 1beta-encoded N-terminal domain of ARF and a C-terminal region of MDM2. ARF-promoted MDM2 degradation is associated with MDM2 modification and concurrent p53 stabilization and accumulation. The functional consequence of ARF-regulated p53 levels via MDM2 proteolysis is evidenced by the ability of ectopically expressed ARF to restore a p53-imposed G1 cell cycle arrest that is otherwise abrogated by MDM2. Thus, deletion of the ARF-INK4a locus simultaneously impairs both the INK4a-cyclin D/CDK4-RB and the ARF-MDM2-p53 pathways.
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              Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest.

              The INK4a (MTS1, CDKN2) gene encodes an inhibitor (p16INK4a) of the cyclin D-dependent kinases CDK4 and CDK6 that blocks them from phosphorylating the retinoblastoma protein (pRB) and prevents exit from the G1 phase of the cell cycle. Deletions and mutations involving INK4a occur frequently in cancers, implying that p16INK4a, like pRB, suppresses tumor formation. An unrelated protein (p19ARF) arises in major part from an alternative reading frame of the mouse INK4a gene, and its ectopic expression in the nucleus of rodent fibroblasts induces G1 and G2 phase arrest. Economical reutilization of coding sequences in this manner is practically without precedent in mammalian genomes, and the unitary inheritance of p16INK4a and p19ARF may underlie their dual requirement in cell cycle control.
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                Author and article information

                Journal
                NEP
                Nephron Physiol
                10.1159/issn.1660-2137
                Nephron Physiology
                S. Karger AG
                1660-2137
                2005
                October 2005
                02 September 2005
                : 101
                : 2
                : p27-p34
                Affiliations
                Department of Nephrology, Tokyo Medical and Dental University, Tokyo, Japan
                Article
                86642 Nephron Physiol 2005;101:p27–p34
                10.1159/000086642
                15990448
                © 2005 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: 45, Pages: 1
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/86642
                Categories
                Original Paper

                Cardiovascular Medicine, Nephrology

                Renal tubule, Ischemia, Cell cycle

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