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Cellular Regulation of Kinin Receptors
Published in Sami I. Said, Proinflammatory and Antiinflammatory Peptides, 2020
Adelbert A. Roscher, Alexander Faussner
Very recently, the genomic organization of the B1 receptor gene has been unraveled. The gene is present as a single copy and is comprised of three exons interrupted by two introns. Sequence analysis of the 5’-flanking region revealed the presence of a consensus TATA box and numerous candidate transcription factor binding sequences (9). Other data appear to indicate that two distinct functional promoters may exist in the human B1 receptor gene (67). Based on the pharmacological evidence, the hypothesis of cytokine-driven upregulation B1 of receptors can be considered to be generally verified, although in some tissues, such as the rat aorta, this never happens (5). It is not yet known whether cytokines directly influence the transcriptional rate of B1 receptors in general or whether other tissue-specific (transcriptional) factors are required for the expression of B1 receptors. The presence of multiple transcription initiation sites in the 5’ region may point to tissue-specific expression and/or alternative splicing of the mRNA of the B1 receptor gene (9). More detailed studies of the putative promoter regions of the B1 receptor gene should provide an avenue to further elucidate the role of this receptor in inflammatory conditions.
Phylogeny of Normal and Abnormal Hemoglobin Genes
Published in S. K. Dutta, DNA Systematics, 2019
A curious feature of the globin genome is the presence of genes which bear a clear structural homology to specific functional genes but which are unable, for one reason or another, to be transcribed or translated.20,21 Three pseudogenes are known in the human globin genome, φα, φβ, and φζ. Rabbit, mouse, and goat are also known to have pseudogenes associated with their globin genomes20 as do the Old World monkeys.22 Originally, a second pseudo-β gene was described but this was later shown to be an artifact of the method when an attempt was made to determine its sequence.23 In many cases the pseudogenes have deletions which shift the reading frame so as to yield either a totally unrecognizable product or to generate terminator codons. There are also abnormalities in the 5′ flanking region.6 One of the two loci originally identified as a second ζ gene was found by DNA sequencing to be a pseudogene by virtue of the fact that it had a terminator in the place of position 6 in the coding region.21
Molecular Mechanisms of Training Effects
Published in Atko Viru, Adaptation in Sports Training, 2017
Almost nothing is known about the contribution of various tissue growth factors in training-induced adaptive protein synthesis. However, there is no background to exclude their possible significance. In related studies, attention has to be paid also to nuclear regulating factors. The muscle-specific proteins have a common DNA sequence of a CC (A + T rich)6GG nucleotide base motif (CArG-box).117 It has been suggested that the CArG motif appears to be the main component for muscle-specific transcriptional stimulation of the contractile protein genes.118 Physiological signals may induce adaptive response through gene expression by interaction of nuclear factors (trans-acting factors) with DNA sequences that regulate the transcription of specific genes.17 The presence of a trans factor in the skeletal muscle is reported.119 In cases where sets of genes have been found to be coordinated by the same trans factor, a consensus sequence in the genes’ 5’-flanking region, which binds this regulatory protein, have been found. It remains to be determined whether the coordinate expression of a subset of muscle genes, which respond to exercise training, may occur by means of recognition of a consensus DNA sequence by an ‘exercise signal’ consisting of a single protein or single oligonucleotide.17
Association of RAGE rs1800624 and rs1800625 gene polymorphisms with predisposition to optic neuritis and optic neuritis together with multiple sclerosis
Published in Ophthalmic Genetics, 2021
Gabriele Kolonaite, Alvita Vilkeviciute, Loresa Kriauciuniene, Greta Gedvilaite, Rasa Liutkeviciene
The receptor for advanced glycation end-product (RAGE) is a multi-ligand receptor involved in inflammation (13). The gene for RAGE is located on chromosome 6p21.3, and at least 30 polymorphisms have been identified till now. Most of the polymorphisms are rare coding changes or located in noncoding regions, including introns and the 5 ′ flanking region (13). Polymorphisms described in the promoter of RAGE gene, the − 374 T > A (rs1800624) and the − 429 T > C (rs1800625) polymorphisms were shown to have a marked effect on in vitro transcriptional activity. The − 429 C, − 374A and 63-bp del alleles resulted in an increase of gene expression of two-, three- and four-fold, respectively (14). Others studies state, that rs1800624 and rs1800625 polymorphisms, influences the transcriptional activity of RAGE promoter, act positively or negatively (15–17).
Transcriptional regulation of CYP3A4 by nuclear receptors in human hepatocytes under hypoxia
Published in Drug Metabolism Reviews, 2020
Xuechun Yuan, Hui Lu, Anpeng Zhao, Yidan Ding, Qiong Min, Rong Wang
Farnesoid X receptor (FXR, NR1H4) has been identified as a key NR in regulating bile acid and lipid metabolism and is regarded as a predictable therapeutic target for those metabolic diseases. FXR would also dimerize with RXRα and then combine with the specific responsive elements in the 5′-upstream regions of its target genes (Urizar et al. 2000). Physiological concentrations of the primary bile acid chenodeoxycholic acid regulate the expression of CYP3A4 via the bile acid receptor FXR in HepG2 cells. Following experiments demonstrated that two functional FXR regulatory sites are located in the 5′-flanking region of human CYP3A4 gene (Gnerre et al. 2004). The regulatory mechanism has been further explored and the results showed that GW4064, as the FXR agonist, could attenuate the expression of CYP3A4 in primary human hepatocytes possibly by enhancing SHP expression and conversely suppressing the PXR and CAR transactivation of CYP3A4 (Zhang et al. 2015), suggesting a potential role of FXR in the PXR- and CAR- mediated CYP3A4. Under hypoxia, FXR could be significantly suppressed in HepG2 cells (Fujino et al. 2009). Although the inhibition is HIF-independent, the possible FXR pathway regulating CYP3A4 under hypoxia should be valued.
Flavin-containing monooxygenase 3 (FMO3): genetic variants and their consequences for drug metabolism and disease
Published in Xenobiotica, 2020
Ian R. Phillips, Elizabeth A. Shephard
Seven variants have been identified in the 5′-flanking region of the FMO3 gene: g.-2650C>A, g.-2589C>T, g.-2543T>A, g.-2177G>C, g.-2106G>A, g.-2099A>G, g.-1961T>C (Koukouritaki et al., 2005). The variants were inferred to segregate into 14 variant haplotypes, six of which were considered common (frequency >1%) (Koukouritaki et al., 2005). Of the six common variant haplotypes, the transcriptional activity in vitro of three was similar to that of the ancestral FMO3 upstream region, whereas one increased transcription eightfold and the remaining two markedly reduced transcription (Koukouritaki et al., 2005). The haplotype that increased transcription was relatively common, being present at frequencies of 29, 11 and 6%, respectively, in Hispanic Americans of Mexican origin, African Americans and whites of northern-European descent, but the two that reduced transcription were each present at low frequency in a single population group, one in the white group, at 4%, and the other in the African-American group, at 1.5% (Koukouritaki et al., 2005). It is not known whether the promoter-region variants affect transcription of the FMO3 gene in vivo.