CALCIUM CONTROLS GENE-EXPRESSION VIA 3 DISTINCT PATHWAYS THAT CAN FUNCTION INDEPENDENTLY OF THE RAS MITOGEN-ACTIVATED PROTEIN-KINASES (ERKS) SIGNALING CASCADE/

Calcium ions are the principal second messenger in the control of gene expression by electrical activation of neurons. However, the full com plexity of calcium-signaling pathways leading to transcriptional activ ation and the cellular machinery involved are not known. Using the c-f os gene as a model system, we show here that the activity of its compl ex promoter is controlled by three independently operating signaling m echanisms and that their functional significance is cell type-dependen t. The serum response element (SRE), which is composed of a ternary co mplex factor (TCF) and a serum response factor (SRF) binding site, int egrates two calcium-signaling pathways. In PC12 cells, calcium-regulat ed transcription mediated by the SRE requires the TCF site and is not inhibited by expression of the dominant-negative Ras mutant, RasN17, n or by the MAP kinase kinase 1 inhibitor PD 98059. In contrast, TCF-dep endent transcriptional regulation by nerve growth factor or epidermal growth factor is mediated by a Ras/MAP kinases (ERKs) pathway targetin g the TCF Elk-1. In AtT20 cells and hippocampal neurons, calcium signa ls can stimulate transcription via a TCF-independent mechanism that re quires the SRF binding site. The cyclic AMP response element (CRE), wh ich cooperates with the TCF site in growth factor-regulated transcript ion, is a target of a third calcium-regulated pathway that is little a ffected by the expression of RasN17 or by PD 98059. Thus, calcium can stimulate gene expression via a TCF-, SRF-, and CRE-iinked pathway tha t can operate independently of the Ras/MAP kinases (ERKs) signaling ca scade in a cell type-dependent manner.