DEPENDENCE OF SV40 LARGE T-ANTIGEN CELL-CYCLE REGULATION ON T-ANTIGEN EXPRESSION LEVELS

Simian virus 40 (SV40) large T antigen (Tag) expression results in reduced percentages of G1-phase cells and increased percentages of S- and G2 + M-phase cells in exponentially growing fibroblast populations as compared with identical cell populations not expressing Tag. This effect is the result of reduced G1 and increased G2 + M cell cycle phase durations caused by Tag [Sladek, T.L. & Jacobberger, J.W. (1992). J. Virol., 66, 1059-1065]. Using recombinant retroviruses to manipulate Tag expression over a 25-fold range, it is shown here that the magnitude of this cell cycle phenotype increases as a function of increasing intracellular Tag concentration. This effect of Tag on the cell cycle is not independent of negative regulation by cellular mechanisms since exponentially growing cell populations producing high and increasing levels of Tag, increase the fraction of cells residing in G1 and decrease the fraction in S and G2 + M as a function of cell density. Therefore, the data in this paper show, first, that Tag is a concentration-dependent, positive cell cycle regulator in exponentially proliferating cells and, second, that endogenous cellular mechanisms negatively regulating the cell cycle in response to cell density override the effect of Tag.