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TA-p63-γ regulates expression of ΔN-p63 in a manner that is sensitive to p53

Oncogene volume 25, pages 2349–2359 (2006)Cite this article

Abstract

Genetic analysis indicates that TP63 is required for establishment and preservation of self-renewing progenitors within the basal layer of several epithelial structures, however, the specific contributions of transactivating (TA-p63) and dominant-negative (ΔN-p63) isoforms remain largely undefined. Recent studies have suggested a model in which TA-p63 plays an important role in the establishment of progenitor populations in which expression of ΔN-p63 contributes to the preservation of self-renewing capacity. Our previous studies indicate that ΔN-p63 is a transcriptional target of p53, however, the absence of overt epithelial deficiencies in p53−/− mice and reports of increased expression of ΔN-p63 in p53−/− mice suggest p53-independent mechanisms also contribute to expression of ΔN-p63. Here, we present data indicating that, prolonged loss of p53 leads to the activation of a p53-independent mechanism for transcriptional regulation of ΔN-p63. This p53-independent mechanism is sensitive to ectopic p53 but not to a p53 mutant that lacks the transactivation domain. We further show that in cells in which p53 is expressed TA-p63-γ protein is destabilized in a manner that is p53 dependent and sensitive to pharmacologic inhibition of the 26S proteosome. Consistent with this observation, we demonstrate that loss of p53 leads to the stabilization of TA-p63-γ that is reversible by ectopic p53. Finally, we present evidence that disruption of TA-p63-γ expression leads to decreased expression of ΔN-p63 and that overexpression of TA-p63-γ was sufficient to enhance the activity of the ΔN-p63 promoter. Taken together, our studies indicate that TA-p63-γ is capable of activating expression of ΔN-p63 and that this mechanism may account for p53-independent expression of ΔN-p63.

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Acknowledgements

We thank Dr Radu V Stan for his help with antibody generation and Dr David Robbins for sharing cell lines. This work was supported by a Scholar's Award from the V Foundation for Cancer Research to JDR. It was further supported by the National Cancer Institute Grant # 1RO1 CA108539 to JDR.

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

    N Li, H Li, P Cherukuri, S Farzan, D C Harmes & J DiRenzo

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  1. N Li
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  2. H Li
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  3. P Cherukuri
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  4. S Farzan
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  5. D C Harmes
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Correspondence to J DiRenzo.

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Li, N., Li, H., Cherukuri, P. et al. TA-p63-γ regulates expression of ΔN-p63 in a manner that is sensitive to p53. Oncogene 25, 2349–2359 (2006). https://doi.org/10.1038/sj.onc.1209270

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