FOS FAMILY MEMBERS INDUCE CELL-CYCLE ENTRY BY ACTIVATING CYCLIN D1

Expression of the fos family of transcription factors is stimulated by growth factors that induce quiescent cells to reenter the cell cycle, but the cellular targets of the Fos family that regulate cell cycle r eentry have not been identified. To address this issue, mice that lack two members of the fos family, c-fos and fosB, were derived. The fosB (-/-) c-fos(-/-) mice are similar in phenotype to c-fos(-/-) mice but are 30% smaller. This decrease in size is consistent,vith an abnormali ty in cell proliferation. Fibroblasts derived from fosB(-/-) c-fos(-/- ) mice were found to have a defect in proliferation that results at le ast in part from a failure to induce cyclin D1 following serum-stimula ted cell cycle reentry. Although definitive evidence that c-Pos and Fo sB directly induce cyclin D1 transcription will require further analys is, these findings raise the possibility that c-Pos and FosB are eithe r direct or indirect transcriptional regulators of the cyclin D1 gene and may function as a critical link between serum stimulation and cell cycle progression.