In order to understand diseases characterized by altered keratinocyte growth and differentiation the precise molecular components governing these pathways will need to be defined. Although in vitro keratinocyte differentiation systems provide readily manipulated tools for studying genetic components of cell growth and differentiation pathways, they often do not accurately recapitulate the regulation of these pathways in an intact mammalian organism. We have recently demonstrated the immortalization of primary human keratinocytes by the helix-loop-helix transcriptional regulatory protein Id1 in vitro. Here we propose the use of a targeted expression system in mouse cutaneous epithelium to study the role of Id1 in regulating keratinocyte growth and differentiation in vivo. We further propose the use of the 2-step model of skin carcinogenesis in genetically altered mice to determine the role of Id1 in the development of cutaneous epithelial neoplasms.
Our specific aims are: 1) To determine the effect of constitutive suprabasal expression of Id1 on skin development. Since Id1 is normally expressed within basal keratinocytes but is not expressed in differentiating suprabasal keratinocytes, we will express this gene constitutively within mouse suprabasal keratinocytes in order to determine the nature of its effect on normal skin development. 2) To determine the contribution of Id1 to cutaneous epithelial tumorigenesis. We will use the 2-step model of mouse skin carcinogenesis to determine whether tumor initiation or progression can be altered by the constitutive expression of Id1 in skin. In addition, since Id1 knockout animals have recently been generated they will be evaluated for their ability to induce cutaneous malignancies in the skin carcinogenesis model to determine the relative contribution of Id1 to cutaneous malignancies. Ultimately, defining the regulatory pathways governing keratinocyte growth and differentiation will allow us to design strategies for targeted disruption of these pathways in cutaneous diseases characterized by altered keratinocyte growth and differentiation or frank neoplasia.
| Alani, Rhoda M; Silverthorn, Courtney F; Orosz, Kate (2004) Tumor angiogenesis in mice and men. Cancer Biol Ther 3:498-500 |
| Sikder, Hashmat; Huso, David L; Zhang, Hong et al. (2003) Disruption of Id1 reveals major differences in angiogenesis between transplanted and autochthonous tumors. Cancer Cell 4:291-9 |
