THE TARGETING OF THE CYCLIN D1 ONCOGENE BY AN EPSTEIN-BARR-VIRUS PROMOTER IN TRANSGENIC MICE CAUSES DYSPLASIA IN THE TONGUE, ESOPHAGUS AND FORESTOMACH

Cyclin D1 in cooperation with its major catalytic partners, cyclin-dep endent kinases cdk4 and cdk6, facilitates progression through the G(1) phase of the eukaryotic cell cycle, in part through phosphorylation o f the retinoblastoma protein, Cyclin D1's oncogenic properties have be en suggested by its cooperation with ras or adenovirus E1a to transfor m cultured cells, as well its overexpression in transgenic mice that l eads to breast cancer. Activated by a number of different mechanisms i n human cancers, the cyclin D1 gene is frequently amplified in squamou s epithelial cancers derived from the head/neck and esophageal regions . In order to study the functional consequences of cyclin D1 overexpre ssion in these squamous epithelial specific sites, we have linked the Epstein-Barr virus ED-L2 promoter to the human cyclin D1 cDNA and util ized this transgene to generate founder lines. This transgene is trans cribed specifically in the tongue, esophagus and forestomach, all shar ing a stratified squamous epithelium. The transgene protein product lo calizes to the basal and suprabasal compartments of these squamous epi thelial tissues, and mice from different lines develop dysplasia, a pr ominent precursor to carcinoma, by 16 months of age in contrast to age -matched wild-type mice, This transgenic model is useful in demonstrat ing cyclin D1 may be a tumor initiating event in aero-upper digestive squamous epithelial tissues.