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

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

AU - Johnson, C M

AU - Hill, C S

AU - Chawla, S

AU - Treisman, R

AU - Bading, H

PY - 1997

Y1 - 1997

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.

AB - 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.

KW - Animals

KW - Calcium

KW - Cyclic AMP Response Element-Binding Protein

KW - DNA-Binding Proteins

KW - Epidermal Growth Factor

KW - Gene Expression Regulation, Enzymologic

KW - Hippocampus

KW - Mice

KW - Mitogen-Activated Protein Kinases

KW - Mutagenesis

KW - Nerve Growth Factors

KW - Nerve Tissue Proteins

KW - Neurons

KW - Nuclear Proteins

KW - PC12 Cells

KW - Pituitary Gland

KW - Promoter Regions, Genetic

KW - Proto-Oncogene Proteins

KW - Proto-Oncogene Proteins c-fos

KW - Rats

KW - Receptors, N-Methyl-D-Aspartate

KW - Serum Response Factor

KW - Signal Transduction

KW - Transcription Factors

KW - Transcription, Genetic

KW - ets-Domain Protein Elk-1

KW - ras Proteins

M3 - Article

C2 - 9236230

VL - 17

SP - 6189

EP - 6202

JO - Journal of neuroscience

JF - Journal of neuroscience

SN - 0270-6474

IS - 16

ER -