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Originally published In Press as doi:10.1074/jbc.M005411200 on August 14, 2000

J. Biol. Chem., Vol. 275, Issue 45, 34938-34945, November 10, 2000
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Regulation of Transcription of the Human Presenilin-1 Gene by Ets Transcription Factors and the p53 Protooncogene*

Martine PastorcicDagger § and Hriday K. DasDagger

From the Dagger  Department of Pharmacology and Neuroscience and  Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, Texas 76107

The expression of the human presenilin-1 cellular gene is suppressed by the p53 protooncogene. The rapid kinetic of the down-regulation has suggested that it may result from a primary mechanism. We show here that p53 also suppresses the transcription of a presenilin-1 promoter-chloramphenicol acetyltransferase reporter synthetic gene in transient infection assays in neuroblastoma (SK-N-SH) and hepatoma (HepG2) cell lines. Only a minimum promoter including sequences from -35 to + 6 from the transcription initiation is sufficient to confer down-regulation. We have previously defined a crucial DNA element controlling 90% of the expression of the gene within the same short area, and the identification of the transcription factors involved should also provide insights into the regulation of PS1 by p53. This region contains an Ets transcription factor binding motif, and a 2-base pair alteration within the core sequence (GGAA to TTAA) of the Ets consensus also reduced transcription by more than 90%. We now show that Ets1 and Ets2 indeed transactivate a PS1 promoter-chloramphenicol acetyltransferase reporter including the (-35 to +6) fragment. Furthermore, in vitro translated Ets2 binds specifically to the -10 Ets motif in electrophoretic mobility shift assays. Therefore, Ets1/2 factors bind specifically to the -10 Ets element and activate PS1 transcription. We also show that the coactivator p300 enhances the activation by Ets1 and Ets2 as well as the repression by p53. p300 is known to interact with p53 as well as with Ets1 and Ets2. We show that p53 does not bind directly to the PS1 promoter. Hence the repression of PS1 transcription by p53 is likely to be mediated through protein-protein interactions.

* This research was supported in part by the University of North Texas Health Science Center at Fort Worth Internal Research Program and by the support of Bank One to the University of North Texas Health Science Center at Fort Worth Institute for Cancer Research.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ To whom correspondence should be addressed: Dept. of Pharmacology and Neuroscience, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX 76107. Tel.: 817-735-0160; Fax: 817-735-2091; E-mail: mpastorc@hsc.unt.edu.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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