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Regulation of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Jiang et al. (2013) have developed a novel mediation analysis approach to identify new expression quantitative trait loci (eQTLs) driving CYP2D6 activity by combining genotype, gene expression, and enzyme activity data. The authors have found 389,573 and 1,214,416 SNP–transcript–CYP2D6 activity trios that are strongly associated for two different genotype platforms, namely, Affymetrix and Illumina, respectively. In the Affymetrix data set, 295 SNPs correlate with at least 20 genes, which are used to check for overlapping with the results of mediation analysis. A total of 289 eQTL hotspots are found to correlate with 1542 gene expression profiles. The Illumina data set has found that 724 SNPs correlate with at least 20 genes, and 719 of the hotspots are significantly correlated with 2444 genes in mediation analysis. Nine hundred thirty-nine and 1420 genes are successfully mapped in the Ingenuity database for two platforms. The majority of eQTLs are trans-SNPs. Five (CCL16, CCL20, CMTM5, IL-6, and SPP1) and 7 (CCL16, CCL20, CKLF, CKLFSF5, EPO, FAM3C, and SPP1) cytokines, 5 (AR, NR1I2/PXR, NR1I3/CAR, NR2F6, and PPARα) and 7 (AR, ESR1, NR1I2/PXR, NR1I3/CAR, PPARα, RORα/NR1F1, and RORγ) nuclear receptors, and 80 and 113 transcription regulators are found to mediate the relationship between genetic variant and CYP2D6 activity for Affymetrix and Illumina data sets. Overlapped eQTL hotspots with the mediators lead to the identification of 64 transcription factors that can regulate CYP2D6 (Jiang et al. 2013). These transcription factors include AATF, ALYREF, ARHGAP35, ASB8, ATF4, CBX4, CEBPG, CSDA, DDIT3, E2F5, ETV7, FOXN3, FOXN3, FUBP1, GPS2, HDAC10, HMGN1, ID1, INVS, IRF9, KANK1, KAT2B, KHDRBS1, KLF12, MAF, MAML2, MEIS2, MLXIPL, MXD4, MYBBP1A, MYCL1, NCOA7, NCOR1, NFIA, NFKB2, NFYA, NOLC1, NPM1, PEX14, PYCARD, SAP18, SATB1, SIM2, SLC2A4RG, SMARCC1, SNAI3, SNW1, SOX5, TCERG1, TCF7L2, TEAD3, TEAD4, TFDP2, TFEB, TOB1, p53, YWHAB, YY1, ZGPAT, ZHX3, ZKSCAN1, ZNF132, ZNF256, and ZNF263 (Jiang et al. 2013). Among them, YY1 has been reported to putatively bind to human CYP2D6 or rat Cyp2d4 promoter and regulate the expression of CYP2D6 (Gong et al. 2013) and Cyp2d4 (Mizuno et al. 2003). This study has provided new insights into the complex regulatory network for hepatic CYP2D6. Addition of the p53 inhibitor cyclic PFT-α in HepG2 cells dose-dependently enhances CYP2D6 and 3A4 activity, whereas addition of the p53 activator NSC 66811 dose-dependently inhibits CYP2D6 and 3A4 activity (Xiao et al. 2015). Further functional and validation studies are certainly needed to verify the regulation of CYP2D6 by these genes.
E2F1 as a molecular drug target in ovarian cancer
Published in Expert Opinion on Therapeutic Targets, 2019
Rossella Farra, Barbara Dapas, Mario Grassi, Fabio Benedetti, Gabriele Grassi
E2F1 belongs to the transcription factor family named E2Fs, characterized by activating (E2F1––E2F3a), repressing (E2F3b––E2F5) or inhibiting (E2F6––E2F8) activities on the transcription of many genes including cell cycle genes [4]. E2F1 (Figure 1(a)) contains a DNA binding domain (DBD) a transactivation domain (TD) and a dimerization domain (DD). DBD allows the binding to gene promoter thus inducing transcription. DD is necessary to bind the dimerization partner (DP) which allows DNA binding. Finally, via TD, E2F1 interacts with its inhibitor retinoblastoma protein (pRB) which binds to E2F1-DP in resting cells. In the presence of proliferation stimuli, pRb is phosphorylated by cyclin D/cdk4-6 (cyclin dependent kinase) kinase and thus released from the complex E2F1/DP (Figure 1(b)). Once detached from pRb, E2F1/DP triggers the transcription of different genes including cyclin E1 that in turn, bound to its cdk2, phosphorylates pRb further allowing E2F1-DP release and activation. Not only E2F1/DP promotes cell growth, it can also activate apoptosis via p53-dependent and p53-independent mechanisms, thus highlighting its double biological role.
Microarray profiling of LncRNA expression in the testis of pubertal mice following morning and evening exposure to 1800 MHz radiofrequency fields
Published in Chronobiology International, 2021
Fenju Qin, Honglong Cao, Chuhan Feng, Tianyuan Zhu, Bingxu Zhu, Jie Zhang, Jian Tong, Hailong Pei
In the present study, we identified 15 differentially expressed lncRNAs that were induced in groups of mice exposed to RF in both the morning and evening. Eight of these differentially expressed lncRNAs participates in pathways regulated by TCFAP4; seven participated in pathways regulated by NFKB2, HINFP, TFDP2, FOXN1, NFKB1, PSIP1, E2F2, E2F5, FKBP4 and EFNA2; six participated in pathways regulated by HES1, PAX5, TCF4, SP2, and NHIH1; and five participated in pathways regulated by E4F1, ELF2, VDR, and RB1.
Emerging circulating MiRNAs and LncRNAs in upper gastrointestinal cancers
Published in Expert Review of Molecular Diagnostics, 2020
Esmat Abdi, Saeid Latifi-Navid, Fatemeh Abdi, Zahra Taherian-Esfahani
MiR-378 was a potential biomarker for the detection of GC with 87.5% sensitivity, 70.73% specificity, and 0.861 AUC. The expression levels of serum miR-378 did not significantly alter between the different stages of TNM. However, the miR-378 expression level in tissues of GC was down-regulated compared to normal tissues, showing that miR-378 may act as a tumor suppressor miRNA in GC [103]. Serum miR-106b rendered 0.856 AUC, 75.0% sensitivity, and 92.5% specificity for distinguishing GC patients from healthy individuals; 0.700 AUC, 87.2% sensitivity, and 45.0% specificity for distinguishing GC patients from benign gastric disease patients; and 0.739 AUC, 75.0% sensitivity, and 68.7% specificity for distinguishing patients with benign gastric disease from healthy individuals. It has also been shown that miR-106b is up-regulated in tissues of GC to act as an oncogene through targeting E2F5, PTEN, p21, and p57 [99]. The plasma miR-195-5 was shown to be significantly down-regulated, with more than 13-fold changes in expression in patients with GC compared to the control group, indicating its potential as a biomarker for GC diagnosis [104]. In addition, the serum levels of miR-148a, miR-146a, and miR-21 expression were associated with the pN stage of GC. A three-miRNA combination could be a biomarker candidate for differentiating GC patients’ LN metastasis from LN-negative GC patients with 0.764 AUC [105]. Song et al. performed a multi-stage, case-control research on two large cohorts to study the potential application of serum miRNAs in the detection of GC. It was revealed that the miR-376 c, miR-221, and miR-744 combination was an effective biomarker for the diagnosis of GC with 82.4% sensitivity and 58.8% specificity. For early detection of GC, the three-miRNA panel revealed a good diagnostic value with 73.3% sensitivity. The three-miRNA panel could concurrently distinguish dysplasia from control individuals with 56.5% sensitivity and 47.8% specificity (Table 2) [106].