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Xenobiotic Biotransformation
Published in Robert G. Meeks, Steadman D. Harrison, Richard J. Bull, Hepatotoxicology, 2020
The mechanisms by which the CYP2 gene families are transcriptionally activated is unknown. For the CYP2B1 and CYP2B2 (PB-inducible) gene families, it is not clear if a receptor is involved with PB induction since no receptor has been identified, induction requires high doses or exposures, and there are no structural-activity relationships for PB-type induction of P450. Several mechanisms may be involved in the increased transcription of the PB-inducible P450. A hierarchy of cis-acting genomic control elements may influence transcription upon interaction with trans-acting factors, such as PB or other PB-type inducer, heme and/or some other tissue-specific factor. For families CYP3 (steroid or PCN-inducible type) and CYP4 (clofibrate-inducible), similarly to the PB-inducible family, increased gene transcription is believed to be involved in induction (Hardwick et al., 1987). The species-, developmental-, sex-, and tissue-specific expression of P450 activities involve additional regulatory mechanisms. The most likely mechanism(s) for this regulation of P450 activities is transcriptional activation via receptors, trans-and cis-acting genomic control elements, and positive- and negative-acting enhancer elements.
New Models to Assess in Vitro Action of Retinoids
Published in Francis N. Marzulli, Howard I. Maibach, Dermatotoxicology Methods: The Laboratory Worker’s Vade Mecum, 2019
ATRA exerts its action by interacting with ligand-inducible trans-acting factors, the RARRα, RARβ and RARRγ, belonging to the steroid/thyroid nuclear receptor superfamily (Petkovich et al., 1987; De Thé et al., 1989, Krust et al., 1989). 9-ds-retinoic acid (9-cis-RA), an isomer of ATRA, interacts with RXRα, RXRβ and RXRγ (Levin et al., 1992; Mangelsdorf et al., 1992). RARs and RXRs bind to specific short DNA sequences, the retinoic acid response elements (RARE), located in the promoter region of target genes, in the form of RAR-RXR heterodimers (Zhang et al., 1992a; Umesono et al., 1991). RXR binds as homodimer to retinoid × response element (RXRE) found in the promoters of genes regulated by 9-cis-retinoic acid (Zhang et al., 1992b). The regulation of gene expression induced by these ligand-dependent trans-acting factors is also related to a further interaction between accessory factors with the cellular transcriptional machinery (Voegel et al., 1996). Additionally, RARs and RXRs may modulate by direct protein-protein interaction the function of other transcription factors such as jun/fos heterodimers or API, interacting with a specific promoter DNA sequence or 12-O-tetradecanoylphorbol acetate (TPA) responsive element (TRE) (Pfahl, 1993).
Changes in Gene Expression During Aging of Mammals
Published in Alvaro Macieira-Coelho, Molecular Basis of Aging, 2017
Studies on the promoter region of genes are beginning to yield data that show that gradual changes occur in the levels of trans-acting factors that bind to specific cis-acting elements. The levels of trans-acting factors, like those of other proteins, are likely to be influenced by changes in hormones, nutrients, and other effectors. This research should, in the next decade, bring deeper insight into the role of genes in the aging process and the cause of aging at the molecular level.
Variability of retinopathy consequent upon novel mutations in LAMA1
Published in Ophthalmic Genetics, 2022
Elena R. Schiff, Nancy Aychoua, Savita Nutan, Indran Davagnanam, Anthony T. Moore, A. G. Robson, C. K. Patel, Andrew R. Webster, Gavin Arno
This report describes the detailed retinal structural and functional consequences of LAMA1 deficiency in four patients from two families, exhibiting intra- and inter-familial variability and showing ERG evidence of cone-rod or cone dystrophy, with preservation of short-wavelength sensitivity. Hypoplasia of the enamel and iris are new findings. Fluorescein angiography is recommended to map the extent of retinal non-perfusion, which can be masked by fundus hypopigmentation. Rhegmatogenous retinal detachment is reported for the first time, secondary to atrophic round microholes in non-perfused retina. Biallelic LAMA1 mutations, even when the genotype is likely to be null, can cause a non-syndromic ocular condition. This, and the variability in the reported family, suggests the action of trans-acting modifying factors. Biallelic mutations should be considered in myopia and retinopathy, even in the absence of systemic signs.
β-Thalassemia Intermedia Caused by the β-Globin Gene 3′ Untranslated Region: Another Case Report
Published in Hemoglobin, 2022
Fan Jiang, Gui-Lan Chen, Jian Li, Xue-Wei Tang, Dong-Zhi Li
The term codon +32 (A>C) mutation has also been reported in an Indian family and a Japanese family. Heterozygotes for this mutation presented with a typical β-thal phenotype in both families [6,7]. The 3′UTR plays an important role in the posttranscriptional regulation of gene expression by affecting mRNA processing, including interactions between mRNA structural components (cis-regulatory sequences) and specific trans-acting factors [8,9]. Therefore, alterations that modify the 3′UTR sequence could lead to errors in the processes of mRNA sub-cellular localization, stability, and efficiency of translation. Using bioinformatics analysis, Sen et al. [7] found that by its binding of two miRNAs, hsa-miR-451a and hsa-miR-3914, at the mutation position, the term codon +32 possibly influences the mRNA stability through recruiting RNA binding proteins. Other mutations in the 3′UTR of the β-globin gene have also been described, and all of them are associated with β+-thal [10,11]. The severity of the disease in β-thal is predominantly determined by the type of the mutation(s) on the β-globin gene. However, the low incidence of rare mutations and the variability of accompanying mutations, make it difficult to predict the clinical severity of compound heterozygotes. Our report, combined with others, provides useful information related to genetic counseling and prenatal diagnosis for the families involved.
First Report of the 3'-Untranslated Region +1506 (A>C) [NM_000518.5: c.*32A>C] mutation on the β-Globin Gene in the Indian Population
Published in Hemoglobin, 2021
Aditi Sen, Venu Seenappa, Prantar Chakrabarti, Tuphan Kanti Dolai
β-Thalassemia (β-thal) is a hereditary blood disorder characterized by anomalies on the β chain synthesis of hemoglobin (Hb) and displays a high level of molecular and clinical heterogeneity [1]. Variants such as point mutations, small indels and large deletions, are reported in the human β-globin gene affecting the expression and resulting in the clinical syndromes of β-thal minor, β-thal intermedia (β-TI) and β-thal major (β-TM) [2]. The outcome of these mutations is the inhibition of efficient β gene transcription and/or mRNA processing, resulting in decreased mRNA levels [3]. Although, the main regulation of gene expression was considered to occur at the transcriptional level, with major roles for transcription factor recruitment/activation at promoter elements, the post-transcriptional events are also equally reported in the β-globin gene regulation [4]. With progressive increase of knowledge about the RNA world, non coding mRNA regions are now known to play an additional unique role in the regulation of gene expression. In this context, a cis-acting regulatory sequence present in either 5′- or 3′-untranslated regions (5′- or 3′-UTRs) of the vast majority of genes recognized by trans-acting factors, and their interaction has shown a strong impact on the post-transcriptional regulation [4].