Calmodulin (CaM) is one of several proteins regulated in a cell cycle-dependent manner. CaM is synthesized at the G1/S boundary and has been implicated in the regulation of cell cycle progression. To elucidate the role of calmodulin in cell cycle control, clonal mouse C127 cell lines transformed with one of four different bovine papilloma virus (BPV)-based vectors were studied. These vectors express a) a chicken CaM gene regulated by its own promoter (CM cells), b) the chicken CaM gene regulated by the inducible human metallothionein-IIa promoter (MCM cells), c) CaM antisense RNA using the Zn2+ inducible mouse metallothionein-I (mMT-I) promoter (AS cells), or d) a rat parvalbumin gene using the chicken CaM promoter (PV cells). C127 cells transformed by BPV-1 alone (BPV cells) are used as a control in each case. Previous studies showed that a 4-fold increase in CaM levels in CM cells shortened the cell cycle by reducing the length of the G1 period. Expression of parvalbumin in PV cells has no effect on cell cycle length, suggesting that increased CAM, and not simply increased Ca2(+)-binding protein, accelerates proliferation. Zn2(+)-induced expression of the chicken CaM gene in MCM cells increased the rate of proliferation, while Zn2(+)-induced expression of high levels of CaM anti-sense RNA stops proliferation at Zn2+ levels that do not affect the growth of BPV cells. In CM cells increased CaM affects cell cycle-dependent level of mRNAs for tubulin, vimentin, and c-myc relative to the levels in BPV cells.(ABSTRACT TRUNCATED AT 250 WORDS)