Carcinogenesis Advance Access originally published online on November 28, 2007
Carcinogenesis 2008 29(2):273-281; doi:10.1093/carcin/bgm258
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Properties of the six isoforms of p63: p53-like regulation in response to genotoxic stress and cross talk with 
Np73
1 INSERM UMR590, Unité d'Oncogenèse et de Progression Tumorale, Centre Léon Bérard, 28 rue Laënnec, F69008 Lyon, France
2 Université de Lyon 1, ISPB, Lyon, F-69008, France
3 International Agency for Research on Cancer, 150 cours A. Thomas, F69372 Lyon Cedex 08, France
4 INSERM U567, Paris, F-75014, France
5 CNRS UMR 8104, Paris, F-75014, France
* To whom correspondence should be addressed. Tel: +33 478 782 806; Fax: +33 478 782 720; Email: carondef{at}lyon.fnclcc.fr
TP63, a member of the TP53 gene family, encodes two groups of three isoforms (
, β and 
). The TAp63 isoforms act as transcription factors. The 
Np63 isoforms lack the main transcription activation domain and act as dominant-negative inhibitors of transactivation (TA) isoforms. To clarify the role of these isoforms and to better understand their functional overlap with p53, we ectopically expressed each p63 isoform in the p53-null hepatocellular carcinoma cell line Hep3B. All TA isoforms, as well as Np63, had a half-life of <1 h when transiently expressed and were degraded by the proteasome pathway. The most stable form was Np63, with a half-life of >8 h. As expected, TA isoforms differed in their transcriptional activities toward genes regulated by p53, TAp63 being the most active form. In contrast, Np63 isoforms were transcriptionally inactive on genes studied and inhibited TA isoforms in a dose-dependent manner. When stably expressed in polyclonal cell populations, TAp63β and isoforms were undetectable. However, when treated with doxorubicin (DOX), p63 proteins rapidly accumulated in the cells. This stabilization was associated with an increase in phosphorylation. Strikingly, in DOX-treated polyclonal populations, increase in TAp63 levels was accompanied by overexpression of Np73. This observation suggests complex regulatory cross talks between the different isoforms of the p53 family. In conclusion, p63 exhibits several transcriptional and stress-response properties similar to those of p53, suggesting that p63 activities should be taken into consideration in approaches to improve cancer therapies based on genotoxic agents.
Abbreviations: DOX, doxorubicin; HCC, hepatocellular corcinoma; PCR, polymerase chain reactions; RT, reverse transcription; TA, transactivation
These authors contributed equally to this work. Received June 28, 2007; revised November 7, 2007; accepted November 8, 2007.