- Because many skin diseases are characterized by disruption of keratinocyte proliferation and differentiation, it is important to understand the mechanisms underlying these processes. While external regulators that activate intracellular signaling pathways are clearly important, these ultimately regulate gene expression by controlling the activity of transcription factors that bind to gene-regulatory regions. POU domain factors, which act by binding to octamer DNA sites, have been shown to be important in terminal differentiation in several organ system. Three such genes Oct1, Tst1, and epidermal specific Skn1 are highly expressed in epidermis. Octamer sites have been found in regulatory regions of several epidermal-specific genes. Indeed, the applicants' studies with Skn1 and Tst1 gene-deleted mice have suggested that the Skn1 gene acts as a repressor of wound front keratinocyte differentiation and that it collaborates with Tst1 to promote normal differentiation of keratinocytes. However, in contrast to mutations of other tissue-specific POU domain genes, no block in differentiation is observed in the Skn1 gene-deleted mice. This likely reflects a functional redundancy between Skn1 and the homologous Oct1 factor that has an identical DNA binding preference. The long-term objective is to understand the role of octamer-binding proteins in epidermal development and function. This is likely to provide insights into regulatory systems in which highly related transcription factors binding to the same DNA sites are co-expressed.
The specific aims are to: 1) Determine the role of Oct-1 in epidermal development and homeostasis, using conditional gene knockout technology; 2) elucidate the mechanisms underlying regulation of keratinocyte differentiation in wound healing by Skn1, using existing gene-deleted mice and novel transgenic mice; 3) identify co-regulators for Skn1a and Skn-1i in epidermis, using a yeast one-hybrid system.
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