TY - JOUR T1 - Calcium Controls Gene Expression via Three Distinct Pathways That Can Function Independently of the Ras/Mitogen-Activated Protein Kinases (ERKs) Signaling Cascade JF - The Journal of Neuroscience JO - J. Neurosci. SP - 6189 LP - 6202 DO - 10.1523/JNEUROSCI.17-16-06189.1997 VL - 17 IS - 16 AU - Claire M. Johnson AU - Caroline S. Hill AU - Sangeeta Chawla AU - Richard Treisman AU - Hilmar Bading Y1 - 1997/08/15 UR - http://www.jneurosci.org/content/17/16/6189.abstract N2 - Calcium ions are the principal second messenger in the control of gene expression by electrical activation of neurons. However, the full complexity of calcium-signaling pathways leading to transcriptional activation and the cellular machinery involved are not known. Using the c-fos gene as a model system, we show here that the activity of its complex promoter is controlled by three independently operating signaling mechanisms and that their functional significance is cell type-dependent. The serum response element (SRE), which is composed of a ternary complex factor (TCF) and a serum response factor (SRF) binding site, integrates two calcium-signaling pathways. In PC12 cells, calcium-regulated transcription mediated by the SRE requires the TCF site and is not inhibited by expression of the dominant-negative Ras mutant, RasN17, nor by the MAP kinase kinase 1 inhibitor PD 98059. In contrast, TCF-dependent transcriptional regulation by nerve growth factor or epidermal growth factor is mediated by a Ras/MAP kinases (ERKs) pathway targeting the TCF Elk-1. In AtT20 cells and hippocampal neurons, calcium signals can stimulate transcription via a TCF-independent mechanism that requires the SRF binding site. The cyclic AMP response element (CRE), which cooperates with the TCF site in growth factor-regulated transcription, is a target of a third calcium-regulated pathway that is little affected by the expression of RasN17 or by PD 98059. Thus, calcium can stimulate gene expression via a TCF-, SRF-, and CRE-linked pathway that can operate independently of the Ras/MAP kinases (ERKs) signaling cascade in a cell type-dependent manner. ER -