Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.30.1 (S1 nuclease)
 3,660 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The vitamin D receptor (VDR) is known to mediate the pleiotropic biological actions of 1,25-dihydroxyvitamin D3 through its ability to modulate the expression of target genes. The regulation of this ligand-activated cellular transcription factor is reported to occur at both transcriptional and posttranslational levels. To begin to address the molecular basis by which the VDR gene is regulated transcriptionally, we report here an initial characterization of the human VDR gene and its promoter. We isolated several overlapping A-phage and cosmid clones that cover more than 100 kb of human DNA and contained the entire VDR gene. The gene is comprised of 11 exons that, together with intervening introns, span approximately 75 kb. The noncoding 5'-end of the gene includes exons 1A, 1B, and 1C. Eight additional exons (exons 2-9) encode the structural portion of the VDR gene product. While primer extension and S1 nuclease-mapping studies reveal several common transcriptional start sites, three unique mRNA species are produced as a result of the differential splicing of exons 1B and 1C. The DNA sequence lying upstream of exon 1A is GC rich and does not contain an apparent TATA box. Several potential binding sites for the transcription factor SP1 and other activators are evident. Fusion of DNA fragments containing putative promoter sequences upstream of the luciferase structural gene followed by transient transfection of these plasmids into several mammalian cell lines resulted in significant reporter activity. Due to the size and complexity of the 5'-end of the VDR gene, we examined the activity of a DNA fragment surrounding exon 1C. An intron fragment 3' of exon 1C conferred retinoic acid responsivity when fused to a reporter gene plasmid, suggesting a molecular mechanism for the previously observed ability of retinoic acid to induce the VDR. The recovery of the gene for the human VDR will enable further studies on the transcriptional regulation of this gene.
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PMID:Structural organization of the human vitamin D receptor chromosomal gene and its promoter. 921 63

The availability of the mouse vitamin D receptor (mVDR) gene has allowed a characterization of a TATA-less promoter containing a cluster of four Sp1 sites named Sp1-1, Sp1-2, Sp1-3, and Sp1-4 (F. Jehan and H. F. DeLuca, 1997, Proc. Natl. Acad. Sci. USA 94, 10138-10143). By means of primer extension analysis, S1 nuclease mapping and ribonuclease protection assay, the start site has been deduced, as has the existence of other minor transcription start sites. Initiation of transcription at the major site is located 4 bp upstream of the 5' end of the mVDR cDNA sequence and very close to the putative Sp1 sites. A second minor promoter might exist between exon 1 and exon 2 of the mVDR gene. The nucleotide sequence of the Sp1 region is well conserved between the mouse, the human, and the chicken VDR genes, suggesting an important role for these Sp1 sites. Gel shift analysis of the four Sp1 sites of the mVDR promoter has confirmed specific binding complexes to Sp1-1, Sp1-2, and Sp1-4 (Sp1-3 rather binds an unknown complex that is unable to bind the canonical Sp1 GGGGCGGGGC). Deletion or mutation of all the Sp1 sites eliminates promoter activity. However, mutation or deletion of individual Sp1 sites did not dramatically change the promoter activity, except for mutation of Sp1-3 that increases promoter activity. We, therefore, conclude that the mVDR promoter is controlled by the Sp1 sites and is the main VDR promoter in intestine and kidney.
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PMID:The mouse vitamin D receptor is mainly expressed through an Sp1-driven promoter in vivo. 1084 4