Sequences in the transcribed region of the c-fos gene have been suggested to control c-fos induction following exposure of cells to mitogens or stimuli that increase intracellular calcium concentrations. Using a mutational analysis we show that putative regulatory elements present in the ®rst intron of the human c-fos gene and the fos-intragenic-regulatoryelement (FIRE) are not required for c-fos regulation by growth factor and calcium signalling pathways in AtT20 and PC12 cells. Removal of the c-fos ®rst intron and the FIRE did not increase the basal level of c-fos mRNA and only moderately reduced the magnitude of calcium-induced transcription mediated by either the entire c-fos promoter or the cAMP response element (CRE). Intragenic mutations did not affect serum response element (SRE)-dependent gene expression induced by calcium signals but caused a superinduction of c-fos expression in nerve growth factor-stimulated PC12 cells. These results indicate that c-fos promoter elements, rather than intragenic sequences, are the principal targets of transcription-regulating signalling pathways. This suggests that CRE-and SRE-bound activators of transcription initiation may also enhance, in a signal-dependent manner, c-fos transcript elongation beyond promoter±proximal pause sites.
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