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Mutant p53 initiates a feedback loop that involves Egr-1/EGF receptor/ERK in prostate cancer cells

Oncogene volume 29, pages 2628–2637 (2010)Cite this article

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Abstract

Early growth response-1 (Egr-1) is overexpressed in human prostate tumors and contributes to cancer progression. On the other hand, mutation of p53 is associated with advanced prostate cancer, as well as with metastasis and hormone independence. This study shows that in prostate cell lines in culture, Egr-1 overexpression correlated with an alteration of p53 activity because of the expression of SV40 large T-antigen or because of a mutation in the TP53 gene. In cells containing altered p53 activity, Egr-1 expression was abolished by pharmacological inhibition or RNAi silencing of p53. Although forced expression of wild-type p53 was not sufficient to trigger Egr-1 transcription, four different mutants of p53 were shown to induce Egr-1. Direct binding of p53 to the EGR1 promoter could not be detected. Instead, Egr-1 transcription was driven by the ERK1/2 pathway, as it was abrogated by specific inhibitors of MEK. Egr-1 increased the transcription of HB-EGF (epidermal growth factor), amphiregulin and epiregulin, resulting in autocrine activation of the EGF receptor (EGFR) and downstream MEK/ERK cascade. Thus, mutant p53 initiates a feedback loop that involves ERK1/2-mediated transactivation of Egr-1, which in turn increases the secretion of EGFR ligands and stimulates the EGFR signaling pathway. Finally, p53 may further regulate this feedback loop by altering the level of EGFR expression.

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Acknowledgements

We thank Dr Ruth Gjerset (Torrey Pines Institute for Molecular Studies, San Diego, CA) for comments and critical reading of the paper. We are grateful to Dr Eileen Adamson and Dr Dan Mercola (University of California, Irvine, CA) for their support and many suggestions. This work was supported by a Grant from NIH/NCI-RO1 CA102688 (V Baron).

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Author notes

  1. L Sauer

    Present address: 2Current address: Prostate Cancer Laboratory, Imperial College of London, Hammersmith Hospital, W120NN, London, UK.,

  2. D Gitenay

    Present address: 3Current address: Centre Léon Bérard, 28 rue Laennec, Batiment Cheney D, 2ème étage, 69008 Lyon, France.,

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  1. Vaccine Research Institute of San Diego, San Diego, CA, USA

    L Sauer, D Gitenay, C Vo & V T Baron

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Correspondence to V T Baron.

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Sauer, L., Gitenay, D., Vo, C. et al. Mutant p53 initiates a feedback loop that involves Egr-1/EGF receptor/ERK in prostate cancer cells. Oncogene 29, 2628–2637 (2010). https://doi.org/10.1038/onc.2010.24

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