EXPRESSION OF CYCLIN D1 IN EPITHELIAL TISSUES OF TRANSGENIC MICE RESULTS IN EPIDERMAL HYPERPROLIFERATION SEVERE THYMIC HYPERPLASIA

To study the involvement of cyclin D1 in epithelial growth and differe ntiation and its putative role as an oncogene in skin, transgenic mire were developed carrying the human cyclin D1 gene driven by a bovine k eratin 5 promoter, As expected, all squamous epithelia including skin, oral mucosa, trachea, vaginal epithelium, and the epithelial compartm ent of the thymus expressed aberrant levels of cyclin D1. The rate of epidermal proliferation increased dramatically in transgenic mice, whi ch also showed basal cell hyperplasia, However, epidermal differentiat ion vr as unaffected, as shown by normal growth arrest of newborn prim ary keratinocytes in response to high extracellular calcium, Moreover, an unexpected phenotype was observed in the thymus, Transgenic mite d eveloped a severe thymic hyperplasia that caused premature death due t o cardio-respiratory failure within 4 months of age. By 14 weeks, the thymi of transgenic mice increased in weight up to 40-fold, representi ng 10% of total body weight, The hyperplastic thymi had normal histolo gy revealing a well-differentiated cortex and medulla, which supported an apparently normal T-cell developmental program based on the distri bution of thymocyte subsets, These results suggest that proliferation and differentiation of epithelial cells are under independent genetic controls in these organs and that cyclin D1 can modulate epithelial pr oliferation without altering the initiation of differentiation program s, No spontaneous development of epithelial tumors or thymic lymphomas was perceived in transgenic mice during their first 8 months of Life, although they continue under observation. This model provides in Five evidence of the action of cyclin D1 as a pure mediator of proliferati on in epithelial cells.