Calcium controls gene expression via three 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 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.
Johnson
C M
CM
Division of Neurobiology, Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 2QH, England.
Hill
C S
CS
Chawla
S
S
Treisman
R
R
Bading
H
H
D000818:Animals; D002118:Calcium / Q000494:pharmacology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016296:Mutagenesis / Q000502:physiology; D009414:Nerve Growth Factors / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000737:chemistry / Q000201:enzymology; D009687:Nuclear Proteins / Q000378:metabolism; D016716:PC12 Cells; D010902:Pituitary Gland / Q000166:cytology; D011401:Promoter Regions, Genetic / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D026362:Serum Response Factor; D015398:Signal Transduction / Q000235:genetics*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology; D050807:ets-Domain Protein Elk-1; D018631:ras Proteins / Q000378:metabolism*
D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; C494113:Elk1 protein, mouse; C494114:Elk1 protein, rat; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D016194:Receptors, N-Methyl-D-Aspartate; D026362:Serum Response Factor; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; C489525:p62TCF protein, mouse; D004815:Epidermal Growth Factor; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins; D002118:Calcium