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      Essential Contribution of Intron Sequences to Ca 2+-Dependent Activation of c-fos Transcription in Pituitary Cells

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          In pituitary cells, c-fos transcription induced by releasing hormones and growth factors results from enhanced initiation of transcription, and sustained elongation of transcripts beyond the first intron. We studied the regulatory role of the first intron of the mouse c-fos gene for the control of its transcription in rat pituitary cells. We showed that the intron contains a block to elongation which is relieved by physiological activators TRH and EGF. By expressing luciferase under the control of the c-fos promoter including the first intron in reporter gene constructs, we demonstrate enhancement of TRH and EGF transcriptional stimulation by intron sequences. Further analysis of Ca<sup>2+</sup> signalling-depending transcription showed that the intron contains control elements in addition to the block to elongation, and that sequences in the first intron can mediate Ca<sup>2+</sup>-stimulated transcription also with a minimal or the SV40 promoter, irrespective of the presence or absence of the intronic block site. Within the c-fos promoter the serum response element and the cAMP response element play a permissive role in Ca<sup>2+</sup>- and cAMP-enhanced transcription of intron containing reporter genes. Specific binding of nuclear proteins to a consensus enhancer binding site (Sp1) within the first intron of c-fos was demonstrated, which might reflect one of the mechanisms that link Ca<sup>2+</sup> and intron sequences to c-fos expression. These findings point towards important functions of intronic sequences in gene transcription control.

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          Most cited references 3

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          c-Jun dimerizes with itself and with c-Fos, forming complexes of different DNA binding affinities.

          The c-Jun and c-fos proto-oncogenes encode proteins that form a complex which regulates transcription from promoters containing AP-1 activation elements. c-Jun has specific DNA binding activity, while c-Fos has homology to the putative DNA binding domain of c-Jun. Following in vitro translation, c-Jun binds as a homodimer to the AP-1 DNA site, while c-Fos fails to dimerize and displays no apparent affinity for the AP-1 element. Cotranslated c-Jun and c-Fos proteins bind 25 times more efficiently to the AP-1 DNA site as a heterodimer than does the c-Jun homodimer. These experiments suggest that in growth factor-stimulated cells c-Jun binds DNA as a dimer with c-Fos as its natural partner. However, overexpression of c-Jun protein in the absence of c-Fos may result in formation of aberrant homodimeric transcription complexes, which could abrogate the normal mechanisms controlling gene expression.
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            A novel calcium signaling pathway targets the c-fos intragenic transcriptional pausing site.

            In many cell types, increased intracellular calcium gives rise to a robust induction of c-fos gene expression. Here we show that in mouse Ltk(-) fibroblasts, calcium ionophore acts in synergy with either cAMP or PMA to strongly induce the endogenous c-fos gene. Run-on analysis shows that this corresponds to a substantial increase in active polymerases on downstream gene sequences, i.e. relief of an elongation block by calcium. Correspondingly a chimeric gene, in which the human metallothionein promoter is fused to the fos gene, is strongly induced by ionophore alone, unlike a c-fos promoter/beta-globin coding unit chimeric construct. Internal deletions in the hMT-fos reporter localize the intragenic calcium regulatory element to the 5' portion of intron 1, thereby confirming and extending previous in vitro mapping data. Ionophore induced cAMP response element-binding protein phosphorylation on Ser(133) without affecting the extracellular signal-regulated kinase cascade. Surprisingly, induction involved neither CaM-Ks nor calcineurin, while the calmodulin antagonist W7 activated c-fos transcription on its own. These data suggest that a novel calcium signaling pathway mediates intragenic regulation of c-fos expression via suppression of a transcriptional pause site.
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              Characterization of two forms of cyclic 3',5'-adenosine monophosphate-dependent protein kinase in rat testicular interstitial cells


                Author and article information

                S. Karger AG
                December 2000
                22 December 2000
                : 72
                : 6
                : 368-378
                aFondation pour Recherches Médicales, University of Geneva Medical School, Geneva, Switzerland; bDepartment of Medicine, University of Texas Health Science Center, San Antonio, Tex., USA
                54606 Neuroendocrinology 2000;72:368–378
                © 2000 S. Karger AG, Basel

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                Page count
                Figures: 6, References: 48, Pages: 11
                Pituitary Cell Biology


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