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p53-dependent downregulation of metastasis-associated laminin receptor

Oncogene volume 21, pages 7478–7487 (2002)Cite this article

Abstract

Based on observations suggesting a role for the tumor suppressor protein p53 in regulating expression of the 67-kDa laminin receptor precursor, 37LRP, we analysed the 37LRP promoter activity in a wild-type p53 (wt p53) ovarian carcinoma cell line and in a cisplatin-resistant subline with mutated p53. We observed an increased promoter activity in wt p53 cells as compared to the mutated-p53 line when the first intron of the 37LRP gene was present in the reporter construct. Cotransfection experiments showed that the promoter is downregulated by both wt and mutated p53. Deletion analysis of the first intron localized an enhancer activity in the first 5′ 214 bp that upregulates both 37LRP and SV40 promoter activity and is repressed by both wt and mutant p53. Cotransfection, mutagenesis and gel-shift experiments identified a functional AP-2 cis-acting element in this intron region that is repressed by increased levels of both wt and mutated p53. Coimmunoprecipitation studies revealed AP-2 in physical association in vivo with both wt and mutated p53, indicating for the first time that interaction of p53 with AP-2 is involved in the repression mechanism and in the regulation of genes involved in cancer growth and progression.

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Acknowledgements

We thank Dr Fabio Castiglioni for help with figures, Mrs Piera Aiello and Mrs Cristina Ghirelli for excellent technical assistance, and Mrs Laura Mameli for manuscript preparation. This work was supported by grants from AIRC. Michele Modugno was supported by a fellowship from FIRC.

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Author notes

  1. Michele Modugno

    Present address: Dept. of Biology, Pharmacia, Nerviano, Milano, Italy

Authors and Affiliations

  1. Department of Experimental Oncology, Molecular Targeting Unit, Istituto Nazionale Tumori, Milan, 20133, Italy

    Michele Modugno, Elda Tagliabue, Elena Ardini, Valeria Berno, Enrico Galmozzi & Sylvie Ménard

  2. Institute for Cancer Research and Treatment, Candiolo, Italy

    Michele De Bortoli

  3. Metastasis Research Laboratory, Sart Tilman, Liège, B-4000, Belgium

    Vincent Castronovo

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  1. Michele Modugno
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Correspondence to Sylvie Ménard.

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Modugno, M., Tagliabue, E., Ardini, E. et al. p53-dependent downregulation of metastasis-associated laminin receptor. Oncogene 21, 7478–7487 (2002). https://doi.org/10.1038/sj.onc.1205957

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