Abstract
Cyclin dependent protein kinases (cdks) are among the most crucial factors controlling cell cycle progression in mammalian cells, and are therefore thought to play an important role in tumorigenisis. In this context, cyclin D1 and E may be of particular relevance since their overexpression leads to an acceleration of G1->S progression and D type cyclins have indeed been shown to be endowed with an oncogenic potential. Here, we show that the ectopic expression of human cyclin E, but not cyclin D1, deregulates DNA synthesis in both yeast and mammalian cells. In yeast, induction of DNA synthesis by cyclin E occurs even under conditions of cell cycle arrest in G1 or G2/M, indicating an uncoupling of DNA replication from cell cycle progression. As a consequence, overexpression of cyclin E is toxic in S. cerevisiae. In rat embryo fibroblasts, the cooperative action of ras and cyclin E induces transformation. These cells, in contrast to those transformed by ras and cyclin D1, show aberrant levels of DNA synthesis. Since cyclin E is commonly overexpressed in a variety of human tumors, these findings may point to a link between the uncontrolled proliferation and the genomic instability typically seen in malignant tumors. Furthermore they reveal significant differences in the functional properties of cyclin E and D1 with respect to cell cycle progression and malignant transformation.