Systematic Isolation of Novel Genes Involved in Regulation of Growth and Differentiation of Slain Cells and Their Relevance to Human Diseases.

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[Objective] In aiming of better understanding of the mechanisms underlying in major human skin diseases and establishing fundamental therapeutic measures, we planned to systematically isolate genes involved in the regulation of growth and differentiation of skin cells.[Methods] RNA differential display was applied to developing mouse skin (12.5 dpc to 16.5 dpc) in which more differentiated epidermal layers are added to existing layer(s) with the progress of development.[Results] We have isolated 6 novel genes, expression levels of which increased during the observation period, and 2 novel genes, which showed a decreasing expression profile during the period. Representative genes are as follows. 2) Hornerin : Hornerin protein has a Ca-binding EF-hand domain in the N-terminal side and repetitive structures in the remaining part. We showed that hornerin protein was co-localized with profilaggrin in keratohyalin granules of granular cells in the skin, tongue, esophagus, and forestomach. When normal human keratinocytes were induced to differentiate by high Ca, expression of hornerin was increased concomitantly with profilaggrin. These results indicate that hornerin is structurally and functionally similar to frofilaggrin and involved in keratinization like profilaggrin. 3) Calmin : Calmin protein has two actin-binding calponin-homology domains at the N-terminus and a transmembrane domain at the C-terminus. It is expressed in the skin, testis, brain (hippocampus, hypothalamus, and Purkinje cells), liver and kidney. The expression levels increase in association with developmental maturation of those organs. 4) tpis : tpis is characterized by possessing tetratriopeptide repeats and presumably involved in differentiation of epidermal keratinocytes. 5) Other related results : Based on these results and techniques, we analyzed developing mouse placenta and succeeded in isolating a number of novel cancer-related gene.