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Carcinogenesis Advance Access published online on August 4, 2005
Carcinogenesis, doi:10.1093/carcin/bgi200
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Published by Oxford University Press 2005
Received January 28, 2005
Revised June 28, 2005
Accepted July 28, 2005

CANCER BIOLOGY

Unique domain functions of p63 isotypes that differentially regulate distinct aspects of epidermal homeostasis

K. E. King 1, R. M. Ponnamperuma 1, M. J. Gerdes 2, T. Tokino 3, T. Yamashita 3, C. C. Baker 2, and W. C. Weinberg 1*

1 Center for Drug Evaluation and Research, FDA, Bethesda, Maryland 20892, USA
2 National Cancer Institute, NIH, Bethesda, Maryland 20892, USA
3 Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan

* To whom correspondence should be addressed.
W. C. Weinberg, E-mail: weinberg{at}cber.fda.gov


  Abstract

p63 is critical for squamous development and exists as multiple isotypes of 2 subclasses, TA and {Delta}N. {Delta}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, {Delta}N- and TA-containing, are expressed and differentially modulated during in vitro murine keratinocyte differentiation. {Delta}Np63{alpha} declines with Ca2+-induced differentiation, while a smaller {Delta}N-form, {Delta}Np63s, persists, suggesting unique functions of the 2 {Delta}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, {Delta}Np63{alpha}, {Delta}Np63p40, TAp63{alpha}, TAp63{gamma} or {beta}-gal were overexpressed in primary murine keratinocytes. Microarray, RT-PCR and western blot analyses revealed that overexpression of {Delta}Np63p40, which lacks the entire {alpha} tail present in {Delta}Np63{alpha}, permits expression of a full panel of differentiation markers. This is in contrast to overexpression of the full length {Delta}Np63{alpha}, which blocks induction of keratin 10, loricrin and filaggrin. These findings support a role for the {alpha}-tail of {Delta}Np63{alpha} in blocking differentiation-specific gene expression. Overexpression of either TAp63 isotype permits keratin 10 and loricrin expression, thus the {alpha}-terminus requires the cooperation of the {Delta}N domain in blocking early differentiation. However, both TA isotypes block filaggrin induction. The {Delta}N-terminus is sufficient to maintain keratinocytes in a proliferative state, as both {Delta}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{alpha} or TAp63{gamma}. 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 tumors with altered expression of p53 family members.

Keywords: p63; p53 homologues; keratinocytes; epidermal differentiation; squamous cell carcinoma.
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