SERUM STARVED V-MOS-TRANSFORMED CELLS ARE UNABLE TO APPROPRIATELY DOWN-REGULATE CYCLINS AND CDKS

Serum deprived v-mos-transformed NIH3T3 cells are unable to enter a tr ue quiescent state, but instead, arrest in the early G1 phase of the c ell cycle, We have analysed several cell cycle regulatory proteins in these G1 arrested cells and show altered regulation in the expression and activity of certain cyclins and cyclin-dependent kinases, In parti cular, p34(cdc2), cyclin A, cyclin D and cyclin E are not appropriatel y down-regulated in serum starved, G1 arrested, v-mos-transformed cell s as compared with quiescent NIH3T3 cells, Furthermore, serum starved v-mos-transformed cells have elevated histone H1 kinase activity assoc iated with cyclin A, cyclin E, p33(cdk2), and p34(cdc2), Using a metal lothionein-inducible c-mos(mu) expression system, we show that c-mos(m u) induction in quiescent NIH3T3 cells causes elevated expression of p 34(cdc2). However, this induction of c-mos(mu) and subsequent expressi on of p34(cdc2) was not sufficient to promote significant entry of cel ls into S phase, Analysis of extracts from serum starved v-H-ras, v-sr c, and tpr-met transformed NIH3T3 cells demonstrates that these oncoge ne-transformed cells also contain elevated levels of p34(cdc2). We pro pose that the altered regulation of these critical cell cycle regulato ry molecules, and specifically the inability to fully downregulate the ir activity, contributes significantly to neoplastic transformation an d subsequent unregulated growth of tumor cells.