ΔNp63α functions as both a positive and a negative transcriptional regulator and blocks in vitro differentiation of murine keratinocytes

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Abstract
Np63 is overexpressed in squamous carcinomas where it is associated with proliferation and is believed to enhance cell growth by blocking p53-mediated transactivation. In normal epithelium, Np63 protein expression is abundant in basal cells and decreases with differentiation. To explore the biological consequences of Np63 overexpression in relation to squamous carcinogenesis, we evaluated its effect on normal squamous differentiation and p53 transactivation function in keratinocytes. Forced overexpression of Np63 in primary murine keratinocytes in vitro inhibits morphological differentiation induced by elevated extracellular [Ca2+], abrogates Ca2+-induced growth arrest, and blocks expression of maturation-specific proteins keratin 10 and filaggrin. This suggests that Np63 overexpression in squamous carcinomas may serve to maintain the basal cell phenotype and promote cell survival. Np63 blocks transactivation of p53 responsive reporter constructs mediated by endogenous or exogenous p53 at 17 h postinfection, as expected. However, at 41 h, when p53-mediated transactivation is diminished, Np63 enhances transactivation of these reporter constructs by 2.2–12-fold over control. Maximal Np63-induced transactivation requires intact p53 responsive elements, but is independent of cellular p53 status. This positive transcriptional function of Np63 appears to be cell-type specific, as it is not observed in primary dermal fibroblasts or Saos-2 cells. These findings support Np63 as a master regulator of keratinocyte differentiation, and suggest a novel function of this protein in the maintenance of epithelial homeostasis.

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