This work is devoted to the study under simple culture conditions of two differentiating mammalian cell types: 1) the human epidermal cell and its close relatives the keratinocytes of other stratified squamous epithelia; this cell type undergoes a program of terminal differentiation to produce a final stage resembling the corneocyte and 2) a preadipose cell line derived from 3T3 and able to differentiate terminally into adipocytes. For both systems we have a number of proteins that are characteristic of the cell in its terminally differentiated state, together with corresponding cDNA and genomic clones. We plan to examine the transition from precursor state, in which the cells are capable of either long term proliferation (human keratinocyte) or indefinite proliferation (3T3 preadipocyte), to a terminally differentiated state in which further division is impossible. We will examine the appearance of specific markers of differentiation in order to understand how the program of differentiation is coordinated. For the epidermal cell we will use cDNA and genomic clones for involucrin and several of the keratins; for adipose differentiation similar clones for glycerophosphate dehydrogenase and two unidentified marker proteins of 13 and 28 kd. This study will include an analysis of the structure of the corresponding genes, the effects of vitamin A on the differentiation of cultured epidermal cells (the regulation of keratin synthesis and of envelope cross-linking), and the effects of growth hormone in promoting the differentiation of preadipose cells. We will attempt to identify the properties of the colony forming epidermal cell, and the alteration of these properties in neoplastic keratinocytes. We will examine the possible role of IGF-1 (the growth hormone induced polypeptide) on clonal expansion of young differentiating adipose cells. These studies are expected to shed light on how differentiation normally leads to the arrest of cell mutiplication and how loss of this coupling leads to neoplasia.
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