Role of Ras/MAP kinases in the control of gene expression by calcium and growth factor signalling pathways

• Main Author: Johnson, C. M.
• Published: University of Cambridge 1997
• Subjects: 572.8
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.605648

One of the earliest consequences of growth factor and neurotransmitter stimulation of neurons is the transcriptional induction of the <I>c-fos</I> proto-oncogene. Previous DNA transfection experiments using plasmids encoding the wild type <I>c-fos</I> gene and successive 5' promoter deletion mutants have identified a number of DNA regulatory elements important for signal-regulated transcription. These include the serum response element (SRE), which is comprised of a ternary complex factor (TCF) and a serum response factor (SRF) binding site, the cyclic AMP response element (CRE) and the sis-inducible element (SIE). However, the regulatory role of these elements in the context of the intact <I>c-fos</I> promoter is less clear. Genomic <I>c-fos</I> DNA constructs containing mutations of specific regulatory elements placed in the natural sequences context of the entire promoter region have been transfected into PC12 cells and then tested for inducibility by calcium and growth factor pathways. In have established that the SRE integrates two calcium signalling pathways. In PC12 cells, calcium-regulated transcription mediated by the SRE requires the TCF site, that can function independently of the Ras/ERK MAP kinase cascade. In ATt20 cells and hippocampal neurons, calcium signals can stimulate transcription through a TCF-independent mechanism that requires the SRF binding site. The CRE is a target of a third calcium-regulated pathway which is also independent of the Ras/ERK MAP kinase cascade in PC12 and AtT20 cells. Therefore, the Ras/ERK MAP kinase cascade does not appear to play a major role in these calcium signalling pathways. In contrast, TCF-dependent transcriptional regulation by nerve growth factor or epidermal growth factor is mediated by a Ras/ERK MAP kinase pathway targeting the TCF Elk-1. These findings suggest a mechanism by which calcium and growth factors can elicit stimulation-specific and cell-type specific patterns of transcriptional events that ultimately determine the biological response of the cell.