Calcium controls gene expression via three distinct pathways that can function independently of the Ras/mitogen-activated protein kinases (ERKs) signaling cascade

C M Johnson, C S Hill, S Chawla, R Treisman, H Bading

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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.
Original languageEnglish
Pages (from-to)6189-202
Number of pages14
JournalJournal of neuroscience
Issue number16
Publication statusPublished - 1997


  • Animals
  • Calcium
  • Cyclic AMP Response Element-Binding Protein
  • DNA-Binding Proteins
  • Epidermal Growth Factor
  • Gene Expression Regulation, Enzymologic
  • Hippocampus
  • Mice
  • Mitogen-Activated Protein Kinases
  • Mutagenesis
  • Nerve Growth Factors
  • Nerve Tissue Proteins
  • Neurons
  • Nuclear Proteins
  • PC12 Cells
  • Pituitary Gland
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-fos
  • Rats
  • Receptors, N-Methyl-D-Aspartate
  • Serum Response Factor
  • Signal Transduction
  • Transcription Factors
  • Transcription, Genetic
  • ets-Domain Protein Elk-1
  • ras Proteins

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