Carcinogenesis Advance Access originally published online on August 4, 2005
Carcinogenesis 2006 27(1):53-63; doi:10.1093/carcin/bgi200
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Carcinogenesis vol.27 no.1 Published by Oxford University Press 2005.
Unique domain functions of p63 isotypes that differentially regulate distinct aspects of epidermal homeostasis
Center for Drug Evaluation and Research, FDA, Bethesda, MD 20892, USA, 1 National Cancer Institute, NIH, Bethesda, MD 20892, USA and 2 Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan
* To whom correspondence should be addressed at: Division of Monoclonal Antibodies, Office of Biotechnology Products, Center for Drug Evaluation and Research, FDA, 29B Lincoln Drive, HFD-123, Building 29B, Room 3NN04, Bethesda, MD 20892-4555, USA. Tel: +1 301 827 0709; Fax: +1 301 827 0852; Email: weinberg{at}cber.fda.gov
p63 is critical for squamous development and exists as multiple isotypes of two subclasses, TA and 
N. Np63 isotypes can antagonize transcription by TAp63 and p53, and are highly expressed in squamous cell cancers. Using mouse keratinocytes as a biological model of squamous epithelium, we show that multiple p63 isotypes, N- and TA-containing, are expressed and differentially modulated during in vitro murine keratinocyte differentiation. Np63
declines with Ca2+-induced differentiation, while a smaller N-form, Np63s, persists, suggesting unique functions of the two N-forms. To investigate the impact of dysregulated p63 expression that is observed in cancers and to define the biological contribution of the different domains of the p63 isotypes, Np63, Np63p40, TAp63, TAp63
or ß-galactosidase were overexpressed in primary murine keratinocytes. Microarray, RT–PCR and western blot analyses revealed that overexpression of Np63p40, which lacks the entire -tail present in Np63, permits expression of a full panel of differentiation markers. This is in contrast to overexpression of the full-length Np63, which blocks induction of keratin 10, loricrin and filaggrin. These findings support a role for the -tail of Np63 in blocking differentiation-specific gene expression. Overexpression of either TAp63 isotype permits keratin 10 and loricrin expression, thus the -terminus requires the cooperation of the N domain in blocking early differentiation. However, both TA isotypes block filaggrin induction. The N-terminus is sufficient to maintain keratinocytes in a proliferative state, as both N forms block Ca2+-mediated p21WAF1 induction and S-phase arrest, while sustaining elevated PCNA levels. No alteration in cell cycle regulation was observed in keratinocytes overexpressing TAp63 or TAp63. Clarifying the functional distinctions between p63 isotypes and domains will help to elucidate how their dysregulation impacts tumor biology and may suggest novel therapeutic strategies for modulating behavior of tumor cells with altered expression of p53 family members.
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