ONCOGENIC ACTIVITY OF CYCLIN D1 REVEALED THROUGH COOPERATION WITH HA-RAS - LINK BETWEEN CELL-CYCLE CONTROL AND MALIGNANT TRANSFORMATION

Circumstantial evidence implicates the putative cell cycle regulator c yclin D1 in the process of malignant transformation. Overexpression of cyclin D1 is observed in mammary carcinomas as a result of gene ampli fication and in parathyroid adenomas and centrocytic B-cell lymphomas as a consequence of chromosomal rearrangements and juxtaposition of th e cyclin D1 gene to strong transcriptional control elements. These fin dings suggest that deregulation of cyclin D1 expression may contribute to malignant transformation in these tumours. To date, however, an on cogenic potential of cyclin D1 has not been demonstrated and the mecha nism of its oncogenic activation remains obscure although overexpressi on of the wild-type protein is likely. We report here that the overexp ression of cyclin D1 induces transformation in primary rat embryo fibr oblasts in cooperation with activated Ha-uas. Cyclin D1/Ha-ras transfo rmed cells are immortalized, show anchorage independence and give rise to fibrosarcomas in nude mice. Our data directly demonstrate that cyc lin D1 is a proto-oncogene that can be activated by transcriptional de regulation. Its previously demonstrated ability to interact with putat ive cell cycle regulators suggests that cyclin D1 defines a new class of proto-oncogenes.