β-catenin signalling modulates proliferative potential of human epidermal keratinocytes independently of intercellular adhesion

Abstract

ABSTRACT We found that cultured human keratinocytes with high proliferative potential, the putative epidermal stem cells, expressed a higher level of noncadherin-associated β- catenin than populations enriched for keratinocytes of lower proliferative potential. To investigate the physiological significance of this, a series of β-catenin constructs was introduced into keratinocytes via retroviral infection. Full-length β-catenin and a mutant containing only nine armadillo repeats had little effect on proliferative potential in culture, the full-length protein being rapidly degraded. However, expression of stabilised, N-terminally truncated β-catenin increased the proportion of putative stem cells to almost 90% of the proliferative population in vitro without inducing malignant transformation, and relieved the differentiation stimulatory effect of overexpressing the E-cadherin cytoplasmic domain. Conversely, β-catenin lacking armadillo repeats acted as a dominant negative mutant and stimulated exit from the stem cell compartment in culture. The positive and negative effects of the β-catenin mutants on proliferative potential were independent of effects on cell-cycle kinetics, overt terminal differentiation or intercellular adhesion, and correlated with stimulation or inhibition of transactivation of a TCF/LEF reporter in basal keratinocytes. We conclude that the elevated level of cytoplasmic β-catenin in those keratinocytes with characteristics of epidermal stem cells contributes to their high proliferative potential.

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Affiliated Institutions

• The Honourable Society of Lincoln's Inn GB

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