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A conserved intronic response element mediates direct p53-dependent transcriptional activation of both the human and murine bax genes

Oncogene volume 21, pages 990–999 (2002)Cite this article

Abstract

Both the human and the mouse bax promoters contain p53 binding sites which are sufficient to confer p53-dependent transcriptional activation in a heterologous setting. Nevertheless in the context of the bax promoter, these sites do not mediate a p53-dependent response, suggesting that bax may not be a direct transcriptional target of p53. Here, data are presented identifying a conserved p53 response element in the first intron of both the human and the murine bax genes. This element both in isolation and in the context of the first intron conferred p53-dependent transcriptional activation upon a minimal promoter. Electrophoretic mobility shift assays demonstrated that this sequence also is capable of mediating sequence specific binding to p53. p53 effectively activated transcription through both human and murine bax gene reporter constructs, whereas deletion of the intronic response element abrogated the p53-responsiveness of both reporters. Interestingly, tumor-derived mutants of p53 which are defective in inducing an apoptotic response retain the ability to activate transcription via the bax intronic p53 site. Since these mutants are transcriptionally inactive on the p53 site in the bax promoter, the ability of these mutants to up-regulating endogenous bax mRNA levels supports a role for the intronic element in p53-dependent up-regulation of bax expression. Taken together, these results show the requirement for a novel intronic element in the p53-dependent transcriptional activation of bax, and demonstrate that bax is indeed a direct and evolutionarily conserved transcriptional target of p53

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Acknowledgements

We thank Bert Vogelstein (Johns Hopkins University) for the wild-type p53 expression plasmid and Karen Vousden (National Cancer Institute) for the 181L and 175P mutant p53 expression plasmids. Ron Magnusson is thanked for help with the recombinant baculovirus infections. Lois Resnick-Silverman is thanked for her help and support. This work was supported by grants from the National Cancer Institute (CA69161), the Breast Cancer Program of the US Army Medical Research and Materiel Command (DAMD-17-97-1-7336, DAMD-17-97-1-7337, and DAMD-17-99-1-9308), and the Peter J Sharp Foundation.

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Authors and Affiliations

  1. Derald H Ruttenberg Cancer Center, Mount Sinai School of Medicine, New York, 10029, NY, USA

    Edward C Thornborrow, Sejal Patel, Anthony E Mastropietro, Elissa M Schwartzfarb & James J Manfredi

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  1. Edward C Thornborrow
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  2. Sejal Patel
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  3. Anthony E Mastropietro
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  4. Elissa M Schwartzfarb
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  5. James J Manfredi
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Correspondence to James J Manfredi.

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The Genbank accession #s are: AF339054 and AF339055.

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Thornborrow, E., Patel, S., Mastropietro, A. et al. A conserved intronic response element mediates direct p53-dependent transcriptional activation of both the human and murine bax genes. Oncogene 21, 990–999 (2002). https://doi.org/10.1038/sj.onc.1205069

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