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Clinical pharmacology of opioids: opioid switching and genetic basis for variability in opioid sensitivity
Published in Nigel Sykes, Michael I Bennett, Chun-Su Yuan, Clinical Pain Management, 2008
Columba Quigley, Joy Ross, Julia Riley
The large range in the absolute values and ratios between morphine and its metabolites could be explained by the wide (up to ten-fold) variability in the expression of UGT2B7 mRNA in human liver biopsy samples.75 Differences in gene expression can be due to alterations in DNA promoter and enhancer sequences which form recognition sites for regulatory DNA binding proteins (transcription factors).76 Transcription of UGT2B7 is regulated by the transcription factor hepatic nuclear factor-1a (HNF1a).75, 77 Coregulatory proteins, such as octamer transcription factor-1 (OCT1)77 and dimerization cofactor of HNF1a (DCOH),78 may also be important.
The Monocyte Chemoattractant Protein Family
Published in Richard Horuk, Chemoattractant Ligands and Their Receptors, 2020
Alberto Mantovani, Silvano Sozzani, Paul Proost, Jo Van Damme
The MCP-1 gene (Figure 2) consists of three exons and two introns.34,55 The translated MCP-1 mRNA codes for a 99 amino acid precursor protein including a 23 amino acids long, mainly hydrophobic leader sequence. The promoter region contains the TATA box, 96 bp upstream of the translation initiation site. The poly-adenylation site (AATAA) is located 353 bp downstream of the stop codon (Figure 2). The GGAAGATCCCT consensus sequence for the kB enhancer element (position -148), which is possibly involved in lipopolysaccharide (LPS) and tumor necrosis factor (TNF) responses, and the ATTTGCGT consensus sequence for the octamer transcription factor (OTF at position -282) were found further in the promoter region.55 In addition to a GC-box (at -126 bp), two TPA-responsive elements (TRE) for the binding of transacting factor AP-1 (TGACTCC and TCACTCA) are found at positions -128 and -156, respectively. Several other kB binding sites and TREs were discovered in the enhancer region, between 2 and 3 kbp upstream of the translation initiation site.56 Promoter and enhancer regions thus contain cis-elements which are possibly important for the regulation of MCP-1 gene transcription. The two cis-elements, essential for the MCP-1 induction and for the maintenance of basal MCP-1 transcriptional activity, were found to be the Sp-1 binding GC-box at position -126 in the promoter region and the kB binding site at position -2672 in the enhancer region, respectively. All other kB binding sites and TREs are to be nonfunctional. The essential nuclear factor-kB (NF-kB) and Sp-1 binding sites can, however, not completely explain the MCP-1 gene transcription since, e.g., in lymphocytes virtually no MCP-1 mRNA is found,24 although the Sp-1 expression is rather high.56
The Roles of MicroRNA in Pancreatic Cancer Progression
Published in Cancer Investigation, 2022
Ramya Devi KT, Dharshene Karthick, Kirtikesav Salem Saravanaraj, M. K. Jaganathan, Suvankar Ghorai, Sanjana Prakash Hemdev
In research conducted by Marin-Muller et al. in pancreatic cancer patients, it has been found that miR- 198 is downregulated in an intricate reciprocal regulatory loop with a tumour-associated antigen, Mesothelin (MSLN) that represses miR-198 through NF-κB-mediated OCT-2 (octamer transcription factor 2) induction. Also, miR-198 repression leads to overexpression of PBX-1 (Pre-B-cell leukemia transcription factor 1) and VCP (Valosin-containing protein). The dysregulated PBX-1/VCP axis leads to increased tumorigenicity (33). Other studies have levels of miR-301a, miR-203, miR-1290, and miR-486-p are high in pancreatic cancer patients and can be used as a biological marker during diagnosis. miR-301a in particular has oncogenic repression of the SMAD4 protein in PDAC patients (32). Additionally, it has been found that miR-200c, which is crucial for the regulation of circulating endothelial cell (CEC) migration and tube formation, is upregulated in CECs derived from pancreatic tumours (34). The target protein of miR-200c is the EMT protein. Xia et al. have discovered that the expression of miR-185 and the TAZ gene is increased in pancreatic cancer patients and that the expression levels of both decreases after transfection with agomiR-185 (20) (Table 1).
Targeting GSK3 signaling as a potential therapy of neurodegenerative diseases and aging
Published in Expert Opinion on Therapeutic Targets, 2018
Przemysław Duda, Janusz Wiśniewski, Tomasz Wójtowicz, Olga Wójcicka, Michał Jaśkiewicz, Dominika Drulis-Fajdasz, Dariusz Rakus, James A. McCubrey, Agnieszka Gizak
One of the hypotheses about SCH pathophysiology considers the role of gray matter loss early at the beginning of SCH [139] and altered neuronal apoptosis [140]. Both mechanisms mentioned above are associated with an increased GSK3β-induced apoptosis [141] and the role of WNT/GSK3β signaling in a proper development of fetal forebrain [142]. Honea and colleagues have reported deficits in a gray and white matter of SCH patients in the left superior and left medial temporal gyri in a voxel-based morphometry [139], whereas Benedetti’s team revealed that a single-nucleotide polymorphism (SNP) in GSK3β promoter (rs334558 T/C with a lower transcriptional activity) resulted in a higher gray matter volumes in the inferior and middle frontal gyri, pre- and postcentral gyri, uncus and inferior occipital gyrus, than in patients without SNP. Another SNP GSK3β variant, rs3755557 T/A, has appeared to be expressed at higher levels because of enhance binding levels of octamer transcription factor 1 (Oct-1) and Pre-B-cell leukemia transcription factor 1 (Pbx-1) to its promoter region. This resulted in a lower gray matter and intracranial volume in healthy individuals [143] which in turn, can be explained by increased Tau and β-catenin phosphorylation by GSK3β leading to decreased neuronal progenitor proliferation [144].
Identification and validation of a novel prognostic circadian rhythm-related gene signature for stomach adenocarcinoma
Published in Chronobiology International, 2023
Lei Qian, Xiaochen Ding, Xiaoyan Fan, Shisen Li, Yihuan Qiao, Xiaoqun Zhang, Jipeng Li
The polycomb gene family (PcG) is a class of transcriptional repressors that is associated with the cell cycle and proliferation, and is an essential component of the memory system that prevents changes in cellular characteristics. The EZH2, a core member of the PcG gene family, mediates H3K27me3 downstream gene silencing, significantly affecting cell proliferation, differentiation, and oncogenesis (Hanson et al. 1999; Müller et al. 2002). In addition, ezh2 was shown to directly regulate circadian rhythms via E-box with the RORE motif in zebrafish. Indeed, the central circadian genes per1a, per1b, cry1aa, and cry1ab were found to be downregulated in ezh2 null mutants and ezh2 morphants, while ezh2 knockdown or overexpression regulated locomotor rhythms of the zebrafish, thus demonstrating that EZH2 is necessary for regulating circadian rhythms (Zhong et al. 2018). Moreover, the core circadian clock gene, Bmal1, regulates cancer progression and chemotherapy susceptibility by recruiting the transcription factor EZH2 to co-bind to the promoter region of TERT, thereby suppressing the molecular mechanism of TERT transcription (Tang et al. 2017). ARNTL, another core component of the circadian clock, can be epigenetically regulated in ovarian cancer through EZH2, which acts as a neoplastic suppressor (Yeh et al. 2014). Multiple causes, including promoter methylation, excessive EZH2 expression, or other variables, may contribute to lower expression of PER1, PER2, PER3, CRY2, and TIM in hepatocellular carcinoma, which in turn are associated with the carcinogenesis process (Lin et al. 2008). Furthermore, the circadian clock gene PER2 serves as a core transcriptional repressor that recruits the polycomb proteins EZH2, SUZ12, and HDAC2 to the octamer transcription factor 1 (OCT1) binding site of TWIST1 and SLUG promoters and to regulate the expression of these epithelial-mesenchymal transition genes (Hwang-Verslues et al. 2013).