DEREGULATED EXPRESSION OF CELL-CYCLE PROTEINS DURING PREMALIGNANT PROGRESSION IN SENCAR MOUSE SKIN

It is now evident that several genes encoding regulatory activities th at control the mammalian cell cycle, particularly some that control th e progression of quiescent cells through G1 and into S phase, are targ ets for alterations that underlie the development of neoplasms. Here, we made a sequential study of alterations in cell cycle protein expres sion and complex formation among cyclin, cyclin dependent kinases (CDK s) and CDK inhibitors (CKIs) during premalignant progression in SENCAR mouse skin tumors. Changes in the level of expression were observed i n positive (cyclin DI, D2, and E2F family members) and negative regula tors (p16(Ink4a), p57(Kip2)) Of the cell cycle. Also, we observed the formation of cyclin/CDK/CKI complexes. The amounts of these proteins a nd complexes increased substantially at specific times during promotio n but not during malignant conversion to carcinomas. These data show t hat deregulation of growth control occurs in benign tumors and that su bsequent mutations not involved cell-cycle regulation are probably nec essary to induce invasive behavior.