Four calmodulin antagonists (W-5, W-7, W-12 and W-13) specifically inhibited the proliferation of two protein-free sublines (P815 PF and Ehrlich PF), although they did not inhibit that of their serum-dependent counterparts. This inhibition of proliferation paralleled the inhibiting activity of the four antagonists against calmodulin. Inhibiting activity of the agents against protein-free cells was cancelled by supplementation of the culture medium with serum. It is suggested that plural signalling pathways switched 'cross-overly' play an important role in the proliferation of protein-free cells. Immunoblotting showed that the soluble calmodulin content in cytoplasm is not changed in protein-free sublines as compared with serum-dependent lines. However, nuclear calmodulin levels of the two protein-free subclones were lower than those of their serum-dependent counterparts. It is suggested that intranuclear calmodulin rather than that in cytoplasm is more important in autonomic proliferation. The internal 'replicon hypothesis' may explain how this autonomic proliferation depends on the nuclear calmodulin pathway.

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