THE NONSTRUCTURAL PROTEINS OF THE AUTONOMOUS PARVOVIRUS MINUTE VIRUS OF MICE INTERFERE WITH THE CELL-CYCLE, INDUCING ACCUMULATION IN G(2)

The nonstructural (NS) proteins of the autonomous parvovirus minute vi rus of mice (prototype strain) are involved in viral DNA replication a nd in the regulation of parvoviral and heterologous promoters. By cons tructing cell lines having integrated the NS coding sequence under the control of an inducible promoter, we were able to demonstrate that NS proteins are toxic, once expressed in the transformed cells. Cell kil ling appears after several days of NS expression, suggesting that NS t oxicity involves cellular factors. In this paper, we show that NS prot eins are cytotoxic and interfere with the cell cycle in proliferating cells only. NS expression is innocuous in resting cells, whereas in gr owing cells, it induces the accumulation of G(2) cells. This cytostati c effect is enhanced upon neoplastic transformation, which sensitizes the cells to NS killing. Moreover, as clones resistant to NS toxicity undergo no alteration of their cycle, this cytostatic effect of NS pro teins could be an early step on the way to cell killing. These observa tions strongly suggest that NS toxicity involves cellular factors asso ciated with the regulation of the cell cycle.