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  • Original Paper
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Positive and negative regulation of ΔN-p63 promoter activity by p53 and ΔN-p63-α contributes to differential regulation of p53 target genes

Oncogene volume 22, pages 7607–7616 (2003)Cite this article

Abstract

Mammary epithelial regeneration implies the existence of cellular progenitors with retained replicative capacity, prolonged lifespan and developmental potency. Evidence exists that ΔN-p63 isoforms preserve these features by modulating p53 activity in basal epithelia. ΔN-p63 mRNA levels decline at the onset of differentiation suggesting that its transcriptional regulation may contribute to the initiation of differentiation. To study transcriptional regulation of ΔN-p63, a 10.3 kbp fragment containing the ΔN-p63 promoter was isolated. We report here that ΔN-p63 is a positive and negative transcriptional target of p53 and ΔN-p63-α, respectively. Disruption of p53 activity or expression abolishes the expression of ΔN-p63-α. This regulation is mediated by a p53-binding element sufficient to confer these activities to a heterologous promoter. Chromatin immune-precipitation indicates that, in asynchronously growing cells, p53 occupies this element. In response to DNA damage, ΔN-p63-α is recruited to this element as transcription of ΔN-p63 declines. Disruption of ΔN-p63-α expression had differential effects on the transcriptional regulation of several p53-target genes. These findings indicate that p53 contributes to the preservation of basal epithelia by driving the expression of ΔN-p63 isoforms. These studies also suggest that in response to genotoxic stress, ΔN-p63-α mediates the silencing of its own promoter thereby altering the pattern of p53-target gene expression.

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Acknowledgements

This work is dedicated to the memory of Dr. Edward Bresnick; collaborator and friend. This work was supported by The General Motors Cancer Research Foundation Scholars Award Program, by the American Cancer Society Institutional Research Grant# IRG-82-003-18 and by the Hitchcock Foundation of Dartmouth Hitchcock Medical Center.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Dartmouth Medical School, 7650 Remsen, Hanover, 03755, NH, USA

    David Christopher Harmes, Julie K Watson, Kelly E Heim, Joshua C Curtin, Anne M Suskind & James DiRenzo

  2. Department of Biochemistry, Dartmouth Medical School, Hanover, 03755, NH, USA

    Edward Bresnick

  3. Dartmouth College, Hanover, 03755, NH, USA

    Emma A Lubin

  4. Dana Farber Cancer Institute, 44 Binney Street, Boston, 02115, MA, USA

    Justin Lamb

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  1. David Christopher Harmes
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Correspondence to James DiRenzo.

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Harmes, D., Bresnick, E., Lubin, E. et al. Positive and negative regulation of ΔN-p63 promoter activity by p53 and ΔN-p63-α contributes to differential regulation of p53 target genes. Oncogene 22, 7607–7616 (2003). https://doi.org/10.1038/sj.onc.1207129

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