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Dopamine Receptors, Signaling Pathways, and Drugs
Published in Nira Ben-Jonathan, Dopamine, 2020
The transcriptional regulation of the DAR genes has been covered in a comprehensive review [11], and some of this information is briefly summarized here. The gene structure of the two DAR classes are dissimilar not only with respect to the organization of their coding regions, but also in their transcriptional regulatory regions. The 5′-regulatory regions of DRD2 and DRD3 contain noncoding exon(s), several kilobases upstream from their coding exons, while those of the DRD1-like have only one noncoding exon and which is separated by a small intron from the coding exon. The promoters of the DAR genes lack functional TATA and CAAT boxes, are GC rich, and have several consensus-binding sites for the transcription factor Sp1. The regulatory region of both DRD2 and DRD3 contain an initiator-like element, indicating transcription initiation from this position, which is under strong negative regulation as has been found in mammalian cell cultures. The 5′-flanking regions of the DRD3 and DRD5 have a much lower GC content than those in the other DAR genes. The transcription of the DAR genes is regulated by cell-type–specific nuclear factors. Some studies have identified several transcription factors (DNA binding proteins) that regulate the DAR genes, with more data generally available on DRD1 and DRD2 than on the other receptors.
Introduction
Published in Emmanuel Opara, NUTRITION and DIABETES, 2005
Hyperglycemia also stimulates release of xanthine oxidase from liver cells into plasma, where this enzyme further contributes to worsening oxidative stress through generation of superoxide ion [48]. There is evidence to suggest that increased superoxide-anion production also activates the hexosamine pathway, which inhibits eNOS activation by O-acetylglucsoaminylation at the Protein Kinase B, a serine threonine protein kinase (Akt) site of the eNOS protein [47]. Shunting of excess glucose into the hexosamine pathway is also believed to result in increased activity of the enzyme O-GlcNAc-β-N-acetylglucosaminidase [49]. This activation likely results in O-acetylglucoaminylation of the transcription factor Sp1 and other glucose-responsive genes, thereby modulating both gene expression and protein function in the vascular wall to contribute to the pathogenesis of diabetic complications.
Vitamin C Alimentation via SLC Solute Carriers
Published in Qi Chen, Margreet C.M. Vissers, Vitamin C, 2020
Damian Nydegger, Gergely Gyimesi, Matthias A. Hediger
The substrate ascorbic acid of SVCT1 and SVCT2 is an important regulator for these transporters. In Gulo−/− mice, which depend on ascorbic acid uptake from the diet, ascorbic acid starvation led to increased mRNA and protein expression of SVCT1 and SVCT2 in the liver, increased expression of SVCT2 in the cerebellum, and increased expression of SVCT1 in the small intestine. Also during development in mice, expression levels and ascorbic acid levels change. In late embryonic and early natal stages, the cortex and cerebellum of these mice have high ascorbic acid levels and low SVCT2 mRNA and protein levels. During adolescence, the expression of SVCT2 mRNA and protein is increased, and the ascorbic acid levels decrease. A development in a similar direction occurs in the liver of the mice: at birth, the expression levels of SVCT1 and SVCT2 are low, increasing over time [2]. It was shown that the hepatocyte nuclear transcription factor HNF1α (hepatocyte nuclear factor 1 homeobox alpha) increases the SVCT1 promotor activity (Figure 3.4) [4,59,60]. HNF1α transcription is inhibited when the NF-κB (nuclear factor–kappa light chain enhancer of activated B cells) signaling pathway is activated. The activated NF-κB pathway leads to increased levels of inflammatory cytokines and cell death [4]. SVCT2 is also regulated in the same manner by HNF1α. SVCT1 and SVCT2 are both regulated on the transcriptional level by transcription factor Sp1. A decrease in Sp1 leads to decreased mRNA and protein levels of SVCT1 and SVCT2 [60]. Other transcription factors such as SP3 and YY1 are also reported to regulate the expression of these transporters [61]. The euchromatin markers H3K4me3 [62,63] and H3K9ac also increase the expression of SVCT1 and SVCT2 [62]. The expression of SVCT1 and SVCT2 depends on many factors, and it is currently an active research topic because of their important role in vitamin C homeostasis.
Small molecule KDM4s inhibitors as anti-cancer agents
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Hongzhi Lin, Qihang Li, Qi Li, Jie Zhu, Kai Gu, Xueyang Jiang, Qianqian Hu, Feng Feng, Wei Qu, Yao Chen, Haopeng Sun
KDM4s are involved in some protein complexes. KDM4A directly binds HDAC and retinoblastoma (pRb) to form a complex. In this complex, KDM4A associated with pRb and class I HDACs and mediated repression (but not promotion as a transcriptional activator) of E2F-regulated promoters in vivo37. One of the E2F-regulated genes aplasia Ras homolog member I (ARHI), which is a tumour suppressive gene, is repressed by this complex46. The downregulation of ARHI may lead to the silence of specificity protein1 (SP1) in advanced breast cancer cells and promotes the metastasis of cancer. The transcription factor SP1 has been considered as an oncoprotein which is highly expressed in early-stage breast cancer. But in advanced breast cancer cells, SP1 is downregulated due to its inhibitory roles for migratory and invasive abilities. Moreover, SP1 also interact with KDM4A strongly which may be a reason for the SP1-inactivity. Taken together, KDM4A seems to play an important role in SP1 downregulation in advanced breast cancer cells. However, in some advanced human bladder cancers, downregulation of KDM4A may promote lymphovascular invasion47.
Small ubiquitin-related modifier (SUMO)ylation of SIRT1 mediates (-)-epicatechin inhibited- differentiation of cardiac fibroblasts into myofibroblasts
Published in Pharmaceutical Biology, 2022
Yingchun Luo, Jing Lu, Zeng Wang, Lu Wang, Guodong Wu, Yuanyuan Guo, Zengxiang Dong
In addition, the transcription factor SP1 can function in the transcriptional regulation of many genes in positive or negative ways (Schäfer et al. 2003; Chou et al. 2005). Previous studies have revealed that oxidation of SP1 was an essential element for the transcriptional regulation of SUMO2 and SUMO3 (Sang et al. 2011). Our research showed that EPI increased protein expression of SP1, SIRT1-SUMO1 in CFs. We also observed that MTM blocked the activation of SIRT1-SUMO1 induced by EPI. Furthermore, MTM blocked the inhibition of EPI on myofibroblasts transformation and collagen synthesis in vitro. The results indicated that SP1 participated in EPI-induced SIRT1-SUMO activation.