The ability to escape from the negative influences of a normal cellular environment may be an important determinant of carcinogenesis. We will examine the role that epithelial/mesenchymal interactions (as mediated by diffusible growth inhibitory factors) and direct gap junctional communication play in the mouse skin system. Our research will employ the following approaches: (1) Keratinocytes of transgenic mice will be made resistant to a number of growth inhibitory and differentiating signals (such as TGF-beta) by specifically expressing truncated, transformation- deficient E1a oncogenes from a keratin promoter. The skin of the transgenics will be examined for structural and physiological alterations as well as tumor development. These in vivo alterations will be correlated with the behavior of cultured keratinocytes derived from these animals. (2) We will specifically enhance or inhibit gap junctional communication in keratinocytes of transgenic mice by expressing either a wild type alpha1 gap junction protein or a dominant negative alpha1 mutant from a keratinocyte-specific promoter. The morphological and functional characteristics of the skin of these mice, as well as their short- and long-term responses to carcinogens and tumor promoters will be examined. (3) We will increase or suppress gap junctional communication of primary keratinocytes in culture by infection with retroviral vectors constitutively expressing the alpha1 gap junction protein or the dominant negative alpha1 mutant. The modified cells will be assayed for their growth/differentiation behavior both in vitro and in vivo, by skin reconstitution experiments. This work will provide important insights on the role of negative growth control mechanisms in epithelial tissue homeostasis.
| Calautti, E; Cabodi, S; Stein, P L et al. (1998) Tyrosine phosphorylation and src family kinases control keratinocyte cell-cell adhesion. J Cell Biol 141:1449-65 |
