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Expression of human p53 requires synergistic activation of transcription from the p53 promoter by AP-1, NF-κB and Myc/Max

Oncogene volume 18, pages 2728–2738 (1999)Cite this article

Abstract

Transcriptional control of p53 expression participates in the generation of appropriate levels of active p53 in response to mitogenic stimulation. This prompted us to study the role of a putative AP-1 and a NF-κB motif in the human p53 promoter for transcriptional regulation. We show that mutation of the AP-1 or the NF-κB motif abolishes transcription from the human p53 promoter in HeLa, HepG2 and adenovirus type 5 E1-transformed 293 cells. In comparison, mutation of the previously characterized Myc/Max/USF binding site in the human p53 promoter reduces the transcription rate fivefold. The AP-1 motif in the human p53 promoter binds c-Fos and c-Jun and the NF-κB motif binds p50NF-κB1 and p65RelA. The cooperative nature of transcriptional activation by these factors was documented by repression of c-fos or NF-κB1 translation: Pretreatment of the cells with a c-fos or p50NF-κB1 antisense oligonucleotide suppresses transcription from the human p53 promoter completely. In addition, we show that (a) the level of endogenous p53 mRNA and (b) transcription from the strictly p53-dependent human mdm2 promoter are reduced in the presence of c-fos, c-jun, p50NF-κB1, p65RelA or c-myc antisense oligonucleotides, underscoring the importance of these transcription factors for the expression of functional p53.

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Acknowledgements

We like to thank Dr Moshe Oren, Weizmann Institute, Israel, for the kind provision of the mdm2 and mdm2m promoters. In addition, we thank Dr Martin Eilers, Institute for Molecular Biology and Tumor Research, University of Marburg, Germany, for the kind provision of the pCX-USF expression construct. Susanne Flaswinkel was a recipient of a DFG-grant of the `Graduiertenkolleg: Zell- und Molekularbiologie normaler und maligner Zellsysteme'. Heike Rumpf was a recipient of a PHD-grant from the `Hans-Böckler Stiftung' and is currently a recipient of an `IPHORES' grant from the University of Essen, Medical School. The technical assistance of Achim Sternberg is gratefully acknowledged. We like to thank Ulla Schmücker for the automated sequencing of our constructs.

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  1. Institute of Molecular Biology (Cancer Research), University of Essen, Medical School, Hufelandstraβe 55, Essen, 45122, Germany

    Hans-Christoph Kirch, Susanne Flaswinkel, Heike Rumpf, Dieter Brockmann & Helmut Esche

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Kirch, HC., Flaswinkel, S., Rumpf, H. et al. Expression of human p53 requires synergistic activation of transcription from the p53 promoter by AP-1, NF-κB and Myc/Max. Oncogene 18, 2728–2738 (1999). https://doi.org/10.1038/sj.onc.1202626

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