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Microphthalmia-Associated Transcription Family Translocation Renal Cell Cancer
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The microphthalmia-associated transcription (MIT) family comprises four basic helix-loop-helix (bHLH) zipper transcription factors (i.e., MITF, TFE3, TFEB, and TFEC) that regulate the expression from promoters containing a DNA response element that includes specific flanking nucleotides in addition to a core E-box element usually bound by bHLH zipper transcription factors.
Dendritic Cells Control the Balance between Tolerance and Autoimmunity
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Simon W. F. Milling, G. Gordon MacPherson
Plasmacytoid pre DCs can be generated in vitro from fetal liver, bone marrow or cord blood CD34+ progenitors in the presence of Flt3L,31 a member of the platelet-derived growth factor (PDGF) receptor superfamily.32 Flt3L acts very early in haematopoiesis, on haematopoietic progenitor cells of the DC lineage, causing expansion of both myeloid and lymphoid progenitor cells.33 Unlike myeloid DCs, however, plasmacytoid pre-DCs do not require GM-CSF for their development and they carry a number of markers expressed in common lymphoid progenitors but not on myeloid cells, including the pre-T cell antigen receptor α chain,34 and λ-like chains.35 The lymphoid-restricted transcription factor Spi-B (spleen focus-forming provirus integration B), which impedes the development of T, B and NK cells, is also uniquely expressed in plasmacytoid DC, not monocyte-derived DC.36 Id (inhibitor of DNA binding) proteins are negative regulators of basic helix-loop-helix (bHLH) transcription factors and inhibit differentiation. Id2 and Id3 proteins inhibit the development of plasmacytoid DCs but not myeloid DCs, or T or B cells when hyper-expressed in CD34+ CD38- progenitors from human fetal liver.37 A greater understanding of these processes would enable better in vitro generation of specific DC subsets and facilitate improved DC-mediated therapy.
The melanocyte and melaninogenesis
Published in Dimitris Rigopoulos, Alexander C. Katoulis, Hyperpigmentation, 2017
Dimitrios Xekardakis, Sabine Krueger-Krasagakis, Konstantinos Krasagakis
PKC-β is involved in the stabilization of tyrosinase and the increase of its enzymatic activity by phosphorylating serine residues on the cytoplasmic domain of tyrosinase. This process seems to lead to the formation of a complex between tyrosinase and TRP-1, which results, as mentioned in the previous paragraph, in the activation and stabilization of tyrosinase. Two further proteins that regulate melaninogenesis are the transcription factor MITF and the melanocortin 1 receptor (MC1R). MITF is very important for the survival of the melanocyte. It is a basic helix–loop–helix and leucine zipper transcription factor, and it has at least nine isoforms. MITF blocks the apoptotic process by enhancing the expression of BCL2, a major antiapoptotic protein in the cell.21 Additionally, it regulates the transcription of the most important melaninogenesis enzymes, PKC-β, tyrosinase, TRP-1, and TRP-2. More specifically, transcription of PKC-β and tyrosinase is controlled by the MITF-M isoform.22 MC1R is the first of the five proteins that belong to the family of the melanocortin receptors, which are G protein–coupled receptors.9 The remaining are MC2R, MC3R, MC4R, and MC5R. Each of them has seven transmembrane domains. MC1R is expressed mostly in melanocytes, but also in other types of cells (keratinocytes, fibroblasts, and endothelial cells).8 It is activated by the hormones ACTH and α-MSH. MC1R regulates melaninogenesis by activating PKA, which induces MITF transcription, and then MITF, by the processes mentioned above, promotes synthesis of eumelanin.15
Identification of inhibitors targeting HIF-2α/c-Myc by molecular docking and MM-GBSA technology
Published in Journal of Receptors and Signal Transduction, 2021
Lijun Feng, Chuance Sun, Xiaohua Sun, Yang Zhao, Rilei Yu, Congmin Kang
Gordan found that pVHL-deficient ccRCC tumors showed enhanced HIF-2α dependent c-Myc activity and improved cell proliferation rates [16], which was opposed to HIF-1α mediated inhibition of c-Myc activity [17]. Increased c-Myc transcriptional activity accelerates the cell cycle progression and promotes tumor growth [18]. Like HIF-2α, c-Myc is also a transcription factor (basic-helix-loop-helix leucine zipper, bHLH-Zip) and a key regulator of cell proliferation that is out of control in many human tumors. In addition, c-Myc must form a heterodimer with Max (another bHLH-Zip protein) and bind to the E-box (CACGTG) motif on DNA in order to function [19,20]. The abnormal expression of HIF-2α and c-Myc in RCC tumors has greatly promoted the development of tumors. In view of the complex expression of various oncogenes in tumor cells, unilateral inhibitory of HIF-2α and c-Myc decreases anticancer effect. Therefore, in order to obtain better anticancer effects, dual or multiple inhibitors are important. At the same time, inhibiting the excessive activity of HIF-2α and c-Myc will be a new direction for treatment of the ccRCC patients.
Role of BMAL1 and CLOCK in regulating the secretion of melatonin in chick retina under monochromatic green light
Published in Chronobiology International, 2020
Jiang Bian, Zixu Wang, Yulan Dong, Jing Cao, Yaoxing Chen
The molecular mechanism by which clock genes regulate the circadian oscillation of melatonin output signal has been basically revealed through previous studies. The positive clock genes Bmal1 and Clock are transcribed and translated into BMAL1 and CLOCK proteins, which are the transcriptional regulators containing the basic helix-loop-helix (bHLH)-PAS protein domain. The BMAL1/CLOCK heterodimer specifically binds on the E-box enhancer located in the 5ʹ flanking region of the promoter of the negative clock genes Pers and Crys, as well as the other clock-control genes, to activate the transcription of these genes. After the transcription and translation of Crys and Pers, the PERS/CRYS heteromultimer blocks the binding of BMAL1/CLOCK to the E-box and inhibits transcriptional activation (Lowrey and Takahashi 2004). As an important clock-control gene, Aanat contains the E-box element in the upstream regulatory sequence of the promoter, which is activated by BMAL1/CLOCK (Chong et al. 2000) and directly drives the synthesis and secretion of melatonin (Iuvone et al. 2005).
Targeting Autophagy In Disease: Recent Advances In Drug Discovery
Published in Expert Opinion on Drug Discovery, 2020
Dasol Kim, Hui-Yun Hwang, Ho Jeong Kwon
MiT/TFE family members (MITF, TFEB, TFE3, and TFEC) are the most recognized master genes of autophagy, as they play a pivotal role in autophagosomal and lysosomal biogenesis [20]. They share a common structure in the basic helix-loop-helix (bHLH) leucine zipper (LZ) dimerization motif, except for TFEC (transcription inhibition rather than activation) [21]. MITF, TFEB, and TFE3 directly bind to the coordinated lysosomal expression and regulation (CLEAR) element [22,23], which is a common feature in the promoter regions of lysosome genes. These proteins are primarily phosphorylated by kinases such as mTORC1 and bound to 14-3-3 protein, which masks their nuclear localization signal (NLS) to maintain them in the cytoplasm [24]. Upon autophagy initiation, the repressive phosphorylation is removed by phosphatases such as calcineurin, resulting in their nuclear translocation for transcription of autophagy/lysosomal genes. Indeed, several studies have revealed that modulation of Mit/TFE family members is a pivotal step in a variety of pathologic phenotypes [25].