Abstract
The TP63 gene, a member of the TP53 gene family, encodes several isoforms with (TAp63) or without (ΔNp63) transactivating properties. Whereas the role of p63 in the normal development of squamous epithelia is well established, its function in other cell types remains to be elucidated. Here, we have analysed the expression of TA and ΔNp63 isoforms in liver cells, by using both primary hepatocytes from wild type and p53-null mice and three human hepatocellular carcinoma (HCC) cell lines, according to the transformation state and the TP53 status of the cells. We observed the expression of ΔNp63 isoforms only in a p53-null context. On the other hand, the expression of TAp63 isoforms was restricted to the HCC cell lines, whatever the TP53 status. We then studied the expression of TP63 upon genotoxic treatment. When treated with UVB or H2O2, hepatocytes did not exhibit any change in p63 mRNA level. At the opposite, upon treatment with topoisomerase II inhibitors (doxorubicin or etoposide), the expression of TAp63 isoforms was clearly induced, independently of the TP53 status of cells. The same treatment did not induce any variation in the expression of ΔNp63 isoforms, both at mRNA and protein levels. In HCC cell lines, doxorubicin or etoposide treatment also resulted in an increase of TAp63 transcripts only. This increase was accompanied by an increase in the intracellular level of TAp63 alpha protein. In parallel, we observed an upregulation of some p53-target genes related to cell cycle regulation, such as WAF1/CIP1, PIG3, 14-3-3σ or GADD45, independently of the TP53 status of cells. In conclusion, we report for the first time that TA and ΔNp63 alpha proteins are present in liver cells. Furthermore, our results suggest that p63 may partially substitute for wild-type p53, in counteracting uncontrolled liver cell proliferation in response to certain forms of DNA-damage.
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Acknowledgements
We thank Drs V Joulin and P Briand for their support to the work. This study was supported by grants from Electricité De France and Association pour la Recherche contre le Cancer, France.
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Petitjean, A., Cavard, C., Shi, H. et al. The expression of TA and ΔNp63 are regulated by different mechanisms in liver cells. Oncogene 24, 512–519 (2005). https://doi.org/10.1038/sj.onc.1208215
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DOI: https://doi.org/10.1038/sj.onc.1208215
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