Genetic analysis of Ras genes in epidermal development and tumorigenesis

Abstract

Proliferation and differentiation of epidermal keratinocytes are tightly controlled to ensure proper development and homeostasis of the epidermis. The Ras family of small GTPases has emerged as a central node in the coordination of cell proliferation in the epidermis. Recent genetic evidence from mouse models has revealed that the intensity of Ras signaling modulates the proliferative capacity of epidermal keratinocytes. Interfering with Ras signaling either by combined elimination of the 3 Ras genes from the basal layer of the epidermis or by overexpression of dominant-negative Ras isoforms caused epidermal thinning due to hypoproliferation of keratinocytes. In contrast, overexpression of oncogenic Ras mutants in different epidermal cell layers led to hyperproliferative phenotypes including the development of papillomas and squamous cell carcinomas. Here, we discuss the value of loss- and gain-of-function studies in mouse models to assess the role of Ras signaling in the control of epidermal proliferation.

Keywords: Ras; epidermis; hyperproliferation; hypoproliferation; mouse models; squamous cell carcinoma.

Figure 1. Ras activity and epidermal proliferation. Genetic elimination of H-Ras, N-Ras and K-Ras from epidermis (Ras KO) causes a defective epidermis characterized by low levels of expression of c-Myc and ΔNp63 and high expression levels of p21^Cip1 and p15^INK4b in the basal layer. In contrast, normal epidermis (wild-type Ras) expresses high levels of c-Myc and ΔNp63 in the basal but not in the suprabasal layer. An opposite pattern of expression is shown by p21^Cip1 and p15^INK4b which are highly expressed in the suprabasal layer but not in the basal layer. In most scenarios, expression of endogenous oncogenic H-Ras and K-Ras mutants in the epidermis do not affect epidermal development. However, when oncogenic Ras mutants are expressed at unphysiologically elevated levels in transgenic mice, they efficiently induce papillomas and squamous cell carcinomas. See text for details.