Calcium signalling and gene expression

A wide variety of compounds acting as extracellular signals cause changes i n the free cytosolic Ca2+ concentration. These factors include hormones, gr owth factors, neurotransmitters, but also nutrient and metabolic activators . Ca2+ signalling is caused by mobilization of Ca2+ from internal stores an d by well controlled and timed Ca2+ influx from the extracellular space. Ca 2+ signals address Ca2+ depend ent enzymes, most importantly Ca2+ sensitive protein kinases and phosphatases. The profound influence of Ca2+ signallin g on gene expression has been recognized a long time ago. As Ca2+ signals a re short-lived when compared to alterations in differentiated gene expressi on, it is generally considered that genes coding for short-lived transcript ion factors (i.e. fos, jun) are the immediate target of Ca2+ signalling. Tr anscription of these immediate early genes (IEG) can be activated without t he need for protein synthesis. Ca2+ signalling affects differentiated gene expression via changes in the absolute and relative abundance of IEG produc ts, which in turn control the expression of differentiated genes. Ca2+ sign als can stimulate both transcriptional initiation as well as transcriptiona l elongation. Initiation of transcription is stimulated by the Ca2+ depende nt phosphorylation of binding proteins addressing two response elements in the promoter of IEGs: the cAMP response element, CRE, and the serum respons e element, SRE. Distinct protein kinases are involved in either case. We st udy the elongation of transcripts of the IEG c-fos beyond the first intron which is favoured by Ca2+ signals, involving mechanisms which still are poo rly understood. We can show that intron sequences contribute to the control of elongation by Ca2+, and that there is a strong interrelation between th e transcription control by the promoter and by the intron.