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Ascorbate and the Hypoxic Response in Cancer
Published in Qi Chen, Margreet C.M. Vissers, Cancer and Vitamin C, 2020
Christina Wohlrab, Caroline Kuiper, Gabi U. Dachs
Hypoxia-inducible factors (HIFs) respond to a reduction in cellular oxygenation by upregulating the production of a plethora of pro-survival factors [12,13]. HIFs are constitutively expressed heterodimeric transcription factors consisting of oxygen-sensitive α subunits (HIF-1α, HIF-2α, and HIF-3α) and a stable HIF-1β subunit, also known as aryl hydrocarbon receptor nuclear translocator (ARNT) [12,13] (Figure 4.2). Under activating conditions, the HIF-α/HIF-1β complex binds to hypoxia-regulated enhancers (HREs, consensus sequence 5′-RCGTG-3′) in gene promoters and recruits the CREB-binding protein (CBP)/p300 coactivator to induce target gene transcription [14,15]. HIF-1 and HIF-2 are well documented, whereas HIF-3 is relatively underexplored. HIF-3 reportedly has transcription factor activity, and a splice variant of HIF-3α is considered to act as a negative regulator of HIF-1 [16,17].
Regulation of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
The mRNA expression and activity levels of CYP2D6 correlate well with each other in vitro and in vivo (Carcillo et al. 2003; Kawakami et al. 2011; Ohtsuki et al. 2012; Rodriguez-Antona et al. 2001; Sakamoto et al. 2011; Temesvari et al. 2012), and the correlation coefficients range from 0.71 to 0.91. Such a high correlation between mRNA and enzyme activity levels of CYP2D6 is also observed for CYP3A4, 1A2, 2B6, and 2C9 (Gerbal-Chaloin et al. 2002; Sy et al. 2002; Temesvari et al. 2012), whose activity levels are known to be governed by the transcriptional regulation of the genes. These results suggest that differential transcriptional regulation of CYP2D6 may contribute to the large interindividual variability in its activity. There are significant correlations observed between CYP2C9 and several regulators including pregnane X receptor (PXR), constitutive androstane receptor (CAR), hepatocyte nuclear factor-4α (HNF-4α), and aryl hydrocarbon receptor nuclear translocator at the mRNA level in a Chinese liver bank with a sample size of 96, but the correlation for CYP2D6 is weak (Wang et al. 2011), suggesting a minor to moderate role of these regulators in the regulation of CYP2D6.
Angiogenesis and Roles of Adhesion Molecules in Psoriatic Disease
Published in Siba P. Raychaudhuri, Smriti K. Raychaudhuri, Debasis Bagchi, Psoriasis and Psoriatic Arthritis, 2017
Asmita Hazra, Saptarshi Mandal
Many of the S100 protein genes are clustered in the epidermal differentiation complex in human chromosome 1q21, which includes the PSORS4 locus, and 13 S100 proteins (S100A2, S100A3, S100A4, S100A6, S100A7, S100A8, S100A9, S100A10, S100A11, S100A12, S100A15, S100B, and S100P) are expressed in normal and/or diseased epidermis (Eckert et al. 2004). Of these, the following are overexpressed in psoriasis; some are regulated under the aryl hydrocarbon receptor nuclear translocator (Arnt)/Hif1b and are known to have angiogenic properties:
Sex differences in the association of measures of sexual maturation to common toxicants: Lead, dichloro-diphenyl-trichloroethane (DDT), dichloro-diphenyl-dichloroethylene (DDE), and polychlorinated biphenyls (PCBs)
Published in Annals of Human Biology, 2021
Casey N. West, Lawrence M. Schell, Mia V. Gallo
The epidemiological literature showing both agonistic and antagonistic effects of organochlorines suggests multiple pathways of effects. Dioxins may affect normal growth and development by binding to the aryl hydrocarbon receptor. Such binding impacts the aryl hydrocarbon receptor nuclear translocator (AhR/ARNT) complex that regulates genes involved in maturation (Schecter et al. 2006; Gore et al. 2015). For non-dioxin like PCBs that do not bind to the aryl hydrocarbon receptor other pathways may be involved. In adult male rats, Leydig cell LH receptor density is reduced by PCB exposure with decreased Leydig cell steroidogenesis and LH-stimulated T production (Murugesan et al. 2005). Human exposure to both PCBs and DDT was associated with increased sex hormone binding globulin and reduced testosterone and LH, suggesting an impact on the hypothalamic pituitary gonadal axis (Grandjean et al. 2012). (Please see Diamanti-Kandarakis et al. (2009) and Bourguignon et al. (2016) for more specific details on endocrine pathways of effect).
Systems analysis of barrier molecule and ARNT-related gene expression regulation in melanoma
Published in OncoImmunology, 2019
Katie M. Leick, Joseph M. Obeid, Stefan Bekiranov, Craig L. Slingluff
Concordant expression of the 8 BMGs that we originally reported10 suggests the possibility of global upregulation, possibly mediated by common transcription factors (TFs) or copy number amplification. In keratinocytes, upregulation of EDC gene expression during atopic dermatitis has been reported to be mediated by the aryl hydrocarbon receptor (AHR) and aryl hydrocarbon receptor nuclear translocator (ARNT),14,15 which heterodimerize and translocate, as an AHR:ARNT complex, to the nucleus.16 Also, there is evidence that EDC gene expression may be enhanced by other TFs, including krüppel-like factor 4 (KLF4), GATA3, GRHL3, AP1, and NRF2, among others.14 However, the effects of these TFs on BMGs outside 1q21.3 or on EDC genes in human melanomas is unclear. We hypothesized that ARNT would promote BMG/EDC expression in melanomas and would thus be overexpressed in BMG/EDCHi melanomas. Alternatively, we hypothesized that copy number variation in the 1q21.3 locus may result in EDC gene overexpression in some patients’ melanomas and may be associated with worse clinical outcomes. To address these hypotheses, we tested whether BMG, EDC, and AHR/ARNT genes are co-expressed in melanomas and are associated with clinical outcome. We also assessed copy number variation at chromosome 1q21.3 and enrichment for TF binding sites in the promoter regions of BMG, EDC, and ARNT associated genes that may explain concordant overexpression of those genes.
Variations in circadian genes and individual nocturnal symptoms of insomnia. The HUNT study
Published in Chronobiology International, 2019
Daniela Bragantini, Børge Sivertsen, Philip Gehrman, Stian Lydersen, Ismail Cüneyt Güzey
The sleep-wake pattern is one of many physiological processes that follow a periodic rhythm of around 24 h. These “circadian” (from Lat. circa= about, diem= day) rhythms are regulated at a molecular level by a group of genes, called circadian genes. The products of these genes form a “molecular clock” which works by negative feedback loops. In a simplified manner, during the day genes CLOCK (Clock Circadian Regulator) and ARNTL (Aryl Hydrocarbon Receptor Nuclear Translocator Like) bind together to promote the transcription of numerous genes. Among these, we find other core circadian genes such as PER (Periodic Circadian Regulator), CRY (Cryptochrome Circadian Regulator) and REV-ERBα (NR1D1, Nuclear Receptor Subfamily 1 Group D Member 1). The role of their corresponding proteins is to interfere with the CLOCK-ARNTL dimer and block their own production (Ko and Takahashi 2006), with the entire feedback loop completing once approximately every 24 h.