Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There are now five known distinct isoforms of TGF-beta with 64-82% identity. Of these, only TGF-beta 1, 2 and 3 thus far have been demonstrated to be expressed in mammalian tissues; TGF-beta 4 has been described only in chicken and TGF-beta 5 only in frog. Although the biological activities of these five isoforms of TGF-beta are indistinguishable in most in vitro assays their sites of synthesis and localization in vivo are often distinct. Expression of the various isoforms is differentially controlled both in vivo, as in development, and in vitro after treatment of cells with steroids, such as oestrogen or tamoxifen, or with retinoids. To investigate the basis of these observations we have cloned and characterized the promoters for the human TGF-beta 1, 2 and 3 genes. Significant differences have been found: whereas the TGF-beta 1 promoter has no TATAA box and is regulated principally by AP-1 sites, both the TGF-beta 2 and 3 promoters have TATAA boxes as well as AP-2 sites and cAMP-responsive elements. Accordingly, TGF-beta 1 gene expression is induced strongly by phorbol esters whereas that of TGF-beta 2 and 3 is induced by forskolin, an activator of adenylate cyclase. Expression of TGF-beta 2 and 3 is often coordinately regulated in vivo in a pattern distinct from that of TGF-beta 1.
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PMID:Multiple forms of TGF-beta: distinct promoters and differential expression. 190 95

Rat GH gene expression is known to be stimulated by several factors, including thyroid hormone and GRF. This effect of GRF appears to be mediated by cAMP resulting from activation of adenylate cyclase by the peptide. The elements of the rat GH gene important for thyroid hormone stimulation and cell-specific expression have been previously mapped using gene transfection techniques. Cell-specific expression of the gene is mediated by two cell-specific elements located from -137 to -107 and from -95 to -65. Sequences mediating thyroid hormone stimulation are thought to be located between -208 and -160. In this study, using three different methods to elevate cAMP levels in cells [forskolin, a direct activator of the adenylate cyclase catalytic subunit; 8-(4-chlorophenylthio)cAMP, a nonmetabolizable cAMP analog; and isobutylmethylxanthine, a phosphodiesterase inhibitor], we show that 5'-flanking DNA of the rat GH gene can mediate stimulation by cAMP (10- to 20-fold). The cAMP-responsive region was mapped to sequences between -104 and +11, which contains the proximal cell-specific element (-95/-65) important for cell-specific expression. Either the -97/-65 or the -104/-47 region of the gene, cloned upstream of a heterologous promoter, conferred only minimal or no activation by cAMP. This suggests that these sequences are not the direct target of cAMP action or that they are insufficient alone to mediate the cAMP response. The cAMP regulatory element (TGACGTCA) is not found between - 104 and +11, and cAMP activation does not appear to act via putative AP-2 elements, since phorbol esters did not stimulate expression.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Identification of an adenosine 3',5'-monophosphate (cAMP)-responsive region in the rat growth hormone gene: evidence for independent and synergistic effects of cAMP and thyroid hormone on gene expression. 247 28

Regulation of GH gene expression by GRF involves cAMP as a second messenger. We have demonstrated that a 500-basepair fragment of the human GH (hGH) gene 5' flanking region can confer cAMP inducibility upon the chloramphenicol acetyltransferase transcription unit in transient transfections of rat pituitary tumor cells treated with forskolin, an activator of adenyl cyclase. The same hGH construct is not induced by forskolin in nonpituitary-derived cells. Experiments with hGH deletion constructs reveal that binding sites for transcription factor AP-2 and the pituitary-specific factor GHF-1 are not required for forskolin stimulation, but that GHF-1 may potentiate the effect. RNA analyses reveal that forskolin also stimulates accumulation of transcripts initiated at the hGH promoter. Other agents that elevate cAMP levels also stimulate hGH expression. Since the hGH 5' flanking region contains no sequences homologous to the cAMP-responsive element of the somatostatin gene, and the AP-2 sites do not appear to be required for the forskolin response, these results suggest that a novel cAMP-responsive element exists within 82 basepairs upstream from the transcriptional start of the hGH gene and that hGH regulation by GRF may involve interaction between a tissue-specific element and a cAMP-inducible element.
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PMID:Induction of human growth hormone promoter activity by the adenosine 3',5'-monophosphate pathway involves a novel responsive element. 254 55

The expression of vascular endothelial growth factor (VEGF) in cultured bovine granulosa cells has been studied. As shown by northern blot analysis, granulosa cells express the VEGF gene. Analysis of the VEGF transcripts by the polymerase chain reaction technique shows that granulosa cells express predominantly the smallest VEGF coding forms (VEGF121 and VEGF164). Since in the promoter region of the VEGF gene there are four potential AP-1 sites and two potential AP-2 sites we have studied if TPA and forskolin could regulate VEGF gene expression. TPA induces VEGF transcription in a time- and dose-dependent fashion. Maximal VEGF mRNA levels are detected 6 h after TPA treatment. Induction apparently requires de novo protein synthesis since it does not occur when translation is inhibited by cycloheximide. Forskolin, a naturally occurring diterpene that activates adenylylcyclase, also increases VEGF mRNA content in a time-dependent manner. Induction does not require de novo protein synthesis and, in contrast to TPA, induction is strongly potentiated by cycloheximide. Luteotrophic hormone, a known activator of adenylylcyclase, also induces VEGF transcription. These results imply that granulosa cells may be a source of VEGF which could play a role in the angiogenic process associated with ovulation and corpus luteum formation.
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PMID:Transcriptional regulation of vascular endothelial growth factor gene expression in ovarian bovine granulosa cells. 846 53

Stem cell factor (SCF) gene expression is regulated by FSH in testicular Sertoli cells. Many functions of FSH are mediated through the second messenger cAMP. We show that cAMP activates transcription of the human SCF promoter in a Sertoli cell line. The human SCF promoter was cloned in cosmid vector pWE15, and its DNA sequence was determined for the promoter region extending 2.3 kilobase pairs upstream from the translation start site at +184 bp. The in vivo messenger RNA (mRNA) start site, by primer-extension studies, was located in exon 1 at +109 bp in human testis mRNA, and at +99 bp in mouse SF7 Sertoli cell line or GC1 germ cell line mRNA. To test which regions of the SCF promoter are necessary for regulation by cAMP, a series of 5'-end deletions of this region were cloned onto the luciferase reporter gene in plasmid pXP1. The SCF promoter region was fused to luciferase downstream (at +120) from its +109 mRNA start site, extending upstream a variable distance to BstXI (-162), BamHI (-313), Bgl2 (-853), or XbaI (-2185). The shortest of these fragments extending only to -162 bp, contains possible SP1 and AP-2 elements. When mouse Sertoli SF7 or human JEG.3 cell lines were transfected with these plasmids, all of the mutants were regulated by 8Br-cAMP or forskolin, as expected for the SCF gene, whereas FSH and TPA had no effect. In the shortest promoter deletion -162, luciferase expression from SF7 cells in serum-free media was at a moderate basal level, but it was induced in six h about 2-fold by 8Br-cAMP, and over 7-fold by forskolin (an adenylate cyclase activator) to high levels, similar to the SV40 positive control promoter. In SCF-luc plasmids extending to -853 or -2185, luciferase expression was still inducible by 8Br-cAMP and forskolin to high levels, but basal promoter activity was repressed to levels over 15-fold lower, in both the absence or presence of testosterone in the media for SF7 cells. The distal portion of the human SCF promoter (between -313 and -853, and also -853 and -2185) inhibits the basal level of transcription, while the proximal region (5' of -162) can mediate activation by cAMP.
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PMID:Human stem cell factor promoter deoxyribonucleic acid sequence and regulation by cyclic 3',5'-adenosine monophosphate in a Sertoli cell line. 894 Mar 64