Journal Article

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

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

in Carcinogenesis

Volume 27, issue 1, pages 53-63
Published in print January 2005 | ISSN: 0143-3334
Published online August 2005 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgi200
Unique domain functions of p63 isotypes that differentially regulate distinct aspects of epidermal homeostasis

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p63 is critical for squamous development and exists as multiple isotypes of two subclasses, TA and ΔN. ΔNp63 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, ΔN- and TA-containing, are expressed and differentially modulated during in vitro murine keratinocyte differentiation. ΔNp63α declines with Ca2+-induced differentiation, while a smaller ΔN-form, ΔNp63s, persists, suggesting unique functions of the two ΔN-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, ΔNp63α, ΔNp63p40, TAp63α, TAp63γ or β-galactosidase were overexpressed in primary murine keratinocytes. Microarray, RT–PCR and western blot analyses revealed that overexpression of ΔNp63p40, which lacks the entire α-tail present in ΔNp63α, permits expression of a full panel of differentiation markers. This is in contrast to overexpression of the full-length ΔNp63α, which blocks induction of keratin 10, loricrin and filaggrin. These findings support a role for the α-tail of ΔNp63α in blocking differentiation-specific gene expression. Overexpression of either TAp63 isotype permits keratin 10 and loricrin expression, thus the α-terminus requires the cooperation of the ΔN domain in blocking early differentiation. However, both TA isotypes block filaggrin induction. The ΔN-terminus is sufficient to maintain keratinocytes in a proliferative state, as both ΔN 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 TAp63α or TAp63γ. 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.

Keywords: Ad-ΔNp63α, overexpression of ΔNp63α mediated by adenovirus; β-gal, β-galactosidase; BrdU, bromodeoxyuridine; FACS, fluorescence activated cell sorting; MOI, multiplicity of infection

Journal Article.  8012 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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