TRANSMEMBRANE SIGNALS AND PROTOONCOGENE INDUCTION EVOKED BY CARCINOGENIC METALS AND PREVENTED BY ZINC

Cd2+ provokes an immediate production of inositol trisphosphate and the release of Ca2+ from internal stores in human fibroblasts and some other mammalian cells. Ni2+, Co2+, Fe2+, and Mn2+ evoke the release of stored Ca2+, but are less potent than Cd2+ (apparent K-0.5 = 40 nM). Zn2+ and Cu2+ competitively inhibit Ca2+ release evoked by Cd2+ without affecting Ca2+ release by hormones such as bradykinin. Zn2+ has the same apparent K-i value (80-90 nM) towards the five agonist metals, which suggests that the metals interact with the same site. Many other divalent cations neither released stored Ca2+ nor affected Cd2+-evoked Ca2+ release. The agonist metals appear to activate phospholipase C via a G protein rather than a tyrosine kinase. The production of reactive oxygen species is probably not involved in Ca2+ release by the metals. Cd2+ and other stimuli that raise cytosolic-free Ca2+ induce cyclic (AMP) production, apparently by activating a calmodulin-dependent adenylyl cyclase. We suggest that an orphan receptor mediates the hormonelike responses to Cd2+ and the other agonist metals. The receptor is referred to as an orphan because its physiological stimulus is unknown. Growth of the fibroblasts in high Zn2+ desensitizes them to the five agonist metals without affecting Ca2+ release by bradykinin or histamine. A several hour incubation in culture medium with normal Zn2+ fully restores responsiveness to the five active metals. Growth in high Zn2+ appears to repress the synthesis of the putative orphan receptor because inhibitors of RNA or protein synthesis, or asparagine-linked glycosylation, prevented the restoration of metal responsiveness. Experiments with lectins and neuraminidase support the view that a cell surface sialoprotein mediates Cd2+ responsiveness. Cd2+ evokes rapid changes in [P-32] incorporation by certain proteins, as would be expected for the activation of a phospholipase C-coupled receptor. Cd2+ and the other metals that trigger hormonelike messenger production, also induce protooncogenes. These observations have revealed a new target for certain metals which is extraordinary with respect to metal potency and specificity. Additionally, the work reviewed here supports the view that certain metals can promote cell growth, which results in part from the fortuitous induction or hormonelike signals.