Regulation of transcription of the human presenilin-1 gene by Ets transcription factors and the p53 protooncogene

被引:58
作者
Pastorcic, M [1 ]
Das, HK
机构
[1] Univ N Texas, Hlth Sci Ctr, Dept Pharmacol & Neurosci, Ft Worth, TX 76107 USA
[2] Univ N Texas, Hlth Sci Ctr, Dept Mol Biol & Immunol, Ft Worth, TX 76107 USA
关键词
D O I
10.1074/jbc.M005411200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 td + 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 PSI by p53. This region,contains an Ets transcription factor binding motif, and a a-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 PSI 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 PSI promoter. Hence the repression of PS1:transcription by p53 is likely to be mediated through protein-protein interactions.
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收藏
页码:34938 / 34945
页数:8
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