Regulation of Transin/Stromelysin and VL30 Gene Expression by Intracellular Calcium

Abstract

Changes in intracellular Ca++ levels are observed as a second messenger in response to a number of cellular agonists, including epidermal growth factor, transforming growth factor beta 1, and endothelin-1. The role of elevated intracellular Ca++ in transducing the effects of these three agonists on gene expression has been studied using two target genes: transin/stromelysin-1 and the endogenous murine retrovirus VL30. Although the effects of EGF and TGF beta 1 on transin/stromelysin-1 mRNA expression appear to be independent of these agonists' effects on intracellular Ca++ levels, elevated Ca++ interacted synergistically with activators of pkC to induce transin expression, even though neither agent alone could induce transin/stromelysin-1 expression. In contrast, the integrated VL30 retrovirus could be induced by Ca++ ionophores alone, and induction of VL30 mRNA by other agonists was blocked if intracellular Ca++ levels were held below a threshold value of 165 nM with Ca++ chelators. Genetic analysis of the VL30 upstream regulatory region indicated that a triple-repeat element present in the VL30 long-terminal repeat could function as an inducible enhancer, but responsiveness to either EGF or pkC activation required the concomitant elevation of intracellular Ca++. Because EGF was capable of inducing expression even in pkC-depleted cells, providing Ca++ levels were elevated, these results indicate that elevated intracellular Ca++ is capable of interacting synergistically with multiple signaling pathways to stimulate increased gene expression.