ABSTRACT
The tumor-promoting phorbol esters (PE) have pleiotropic physiological effects on mammalian cells. 1 Indeed, they have been long recognized to possess mitogenic activity in experimental cultured cell systems. 2 , 3 Either alone or, more commonly, in concert with agents which raise the concentration of cytosolic-free Ca2+ ([Ca2+]i), these compounds have been shown to be potent mitogens. In most experimental systems, using growth-arrested primary (or in some cases, immortalized) cell lines, both signals are required to achieve the maximal proliferative response. 4 This suggests that phorbol esters, which by themselves do not raise [Ca2+]i, cooperate in some way with agents that do. For example, in lymphocytes, one of the best-studied systems, PE treatment alone does not lead to proliferation, as measured by [3H]-thymidine incorporation. Neither does exposure to a calcium ionophore, such as A23187 or ionomycin. However, when the ionophore and PE are added concurrently, a potent mitogenic effect is observed. 4 These observations suggest that PEs are either amplifying a common pathway of cell activation or, more likely, are stimulating a component of the pathway that is not optimally activated solely by raising the [Ca2+]i.
