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Microphthalmia-Associated Transcription Family Translocation Renal Cell Cancer
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
TFE3 and TFEB belong to the MIT family consisting of MITF, TFE3, TFEB, and TFEC. These transcription factors share a bHLH DNA-binding domain and similar target genes. Fusion of TFE3 or TFEB with ASPSCR1 or MALAT1 (or related genes) leads to their overexpression, which underlies the development of Xp11 tRCC and t(6;11) RCC (collectively known as MIT family tRCC) as well as other tumors (e.g., alveolar soft part sarcoma, melanoma, clear cell sarcoma, angiomyolipoma, and perivascular epithelioid cell tumor [PEComa]) [8]. Indeed, TFE3 gene fusions have been identified in PEComas of the kidney and soft tissue [9].
Effects of Retinoids at the Cellular Level (Differentiation, Apoptosis, Autophagy, Cell Cycle Regulation, and Senescence)
Published in Ayse Serap Karadag, Berna Aksoy, Lawrence Charles Parish, Retinoids in Dermatology, 2019
Activation of RAR and PPAR by RA is crucial for induction of neuronal differentiation, and various target genes have been reported to be involved in this process (25,26). RA, through its effectors, directly regulates expression of subset of homeotic genes (Hox) Hoxa-1, Hoxb-2, and Wnt-1 (27). These master control genes specify the body plan and regulate the development and morphogenesis of higher organisms. In addition, RA also indirectly regulates achaete-scute family bHLH transcription factor 1 gene (ASCL1), Neurogenin 1 (NEUROG1), neuronal differentiation 1 (NeuroD1), N-cadherin/cadherin 2 (CDH2), and pre-B-cell leukemia transcription factors or PBX homeobox genes (Pbx) (7).
Secreted effectors of the innate mucosal barrier
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Michael A. McGuckin, Andre J. Ouellette, Gary D. Wu
Notch signaling, which controls cell fate decisions in many different tissues, also determines secretory (goblet, enteroendocrine, tuft and Paneth cells) versus absorptive cell lineage development in the intestinal epithelium (Figure 4.3). Activation of one of four Notch receptors by any one of several ligands, from either the Delta or Jagged/Serrate families, results in the proteolytic cleavage and liberation of the Notch intracellular domain from the plasma membrane by γ-secretase. The Notch intracellular domain subsequently translocates into the nucleus where it forms a transcriptional activation complex with RBP-jk (also known as CSL), displacing histone deacetylase corepressors and recruiting histone acetyltransferases, leading to transcriptional activation of Notch target genes such as hairy/enhancer of split (HES). HES1, a basic helix-loop-helix (bHLH) transcriptional repressor, inhibits the expression of another bHLH factor, ATOH1 (Math1 for mouse, Hath1 for human), suppressing secretory cell lineage differentiation in the intestinal epithelium and leading to disproportionate numbers of absorptive enterocytes. The intestinal epithelium of Math1 knockout mice is populated only by absorptive enterocytes. By contrast, the inhibition of Notch signaling by CSL gene knockout, or with γ-secretase inhibitors, induces Math1 expression, leading to the conversion of all epithelial cells into goblet cells. HES1 knockout mice, although embryonic lethal, show an increase in goblet, enteroendocrine, and Paneth cells, with decreased numbers of absorptive enterocytes. Likely downstream of Math1 is the zinc finger transcriptional repressor, Gfi1, which is involved in the generation of Paneth and goblet, but not enteroendocrine, cells. Interestingly, the loss of Kruppel-like factor 4 (Klf4), a zinc finger transcription factor that is repressed by Notch signaling, leads to reduced goblet cell numbers.
Rodent genetic models of Ah receptor signaling
Published in Drug Metabolism Reviews, 2021
Rachel H. Wilson, Christopher A. Bradfield
The obligate binding partner of the AHR, ARNT, has been modified in several ways to further elucidate the role of this protein in PAS sensor signaling (Figure 7, Table 5). Initial studies focused on generating Arnt null models (Kozak et al. 1997; Maltepe et al. 1997). Two such models have been generated independently using ESCs from 129 mice. One model was developed through a gene targeting approach that created a disruption of the bHLH domain with the insertion of a NeoPGK cassette (Maltepe et al. 1997). In another, homologous recombination was used to remove the bHLH exon (Kozak et al. 1997). As homozygotes, both models were found to die in utero between embryonic days 9.5 and 10.5, while heterozygous littermates survived. This early embryonic lethality was soon reveled to be a function of the fact that ARNT had multiple dimerization partners in addition to the AHR. Notably, ARNT is now known to dimerize with HIFs, and through these interactions are essential in biological processes including the hypoxia response, glucose metabolism, blood cell development, and angiogenesis (Gradin et al. 1996; McIntosh et al. 2010). Because Arnt null animals are embryonic lethal and do not produce viable offspring, their use has proven more common in developing an understanding of non-AHR pathways. Such studies are not reviewed here.
Targeting ubiquitin protein ligase E3 component N-recognin 5 in cancer cells induces a CD8+ T cell mediated immune response
Published in OncoImmunology, 2020
Mei Song, Chao Wang, Huan Wang, Tuo Zhang, Jiuqi Li, Robert Benezra, Lotfi Chouchane, Yin-Hao Sun, Xin-Gang Cui, Xiaojing Ma
In contrast to the strong paracrine involvement of CD8+ T-mediated immunity in UBR5-regulated tumor growth, the metastatic process driven by UBR5 appears to be primarily cell-intrinsic. Our data demonstrate that the annulling of Ubr5 in 4T1 cells is causative for the loss of E-cadherin expression and impairs the tumor cells’ mesenchymal to epithelial transition (MET) and their ability to colonize in secondary organs. This effect is controlled by UBR5 principally through transcriptional regulation of the key EMT regulators ID1 and ID3. The result is the maintenance of Ubr5−/- tumor cells in the mesenchymal state lacking E-cadherin expression, thus unable to complete MET and take roots in the lungs. It is thus of great importance to further understand how UBR5 loss leads to ID1/ID3 downregulation. Given the mechanism of UBR5’s action, it is possible that loss of UBR5 may lead to the stabilization of a repressor which inhibits ID1/ID3 expression. ATF3 is a well-characterized, known repressor of ID1 expression.24 It will be interesting to determine if UBR5 destabilizes ATF3. It is equally possible that loss of UBR5 leads indirectly to the loss of a positively acting transcription factor that controls ID1/ID3 expression. A variety of factors that control ID1 expression in TNBC cells have been identified. The basic helix-loop-helix (bHLH) transcription factor Lyl1 and CREB1, a widely expressed transcription factor, and a suspected oncogene, interact and form a molecular complex. The histone acetyltransferases p300 and CBP are recruited to this complex. Together they activate CREB1 target promoters such as Id1, Id3, cyclin D3, Brca1, Btg2, and Egr1.25
Circadian gene methylation profiles are associated with obesity, metabolic disturbances and carbohydrate intake
Published in Chronobiology International, 2018
Omar Ramos-Lopez, Mirian Samblas, Fermin I. Milagro, Jose I. Riezu-Boj, A.B. Crujeiras, J. Alfredo Martinez, MENA Project
Additional components of the molecular clock stimulated by the BMAL1/CLOCK complex include ROR and REV-ERBα, which bind ROR DNA elements to stimulate or repress transcription, respectively (Jetten 2009; Papazyan et al. 2016). Other transcriptional targets of CLOCK-BMAL1 involve the PAR-bZip family members and the bHLH proteins (Gachon 2007; Kato et al. 2014). In this investigation, methylation levels at RORA and BHLHE40 (also known as DEC1) negatively correlated with BMI, HOMA-IR, MAP and energy intake derived from carbohydrates. Regarding the regulatory functions of RORA in adiposity and energy metabolism, contradictory results have been reported. For example, homozygous staggerer (sg/sg) mice, which have low and dysfunctional expression of Rora in all tissues, displayed decreased dyslipidemia and reduced adiposity and were protected from the development of diet-induced obesity, liver steatosis, adipose-associated inflammation and insulin resistance (Lau et al. 2008; Kang et al. 2011; Lau et al. 2015). Moreover, improved insulin sensitivity and enhanced glucose uptake in skeletal muscle have been reported in sg/sg mice through regulation of the AKT signaling cascade (Lau et al. 2011). On the other hand, liver-specific Rora-deficient mice underwent liver steatosis, obesity and insulin resistance when challenged with a high-fat diet (Kim et al. 2017). Also, loss of Rora led to overactivation of the sterol-regulatory element-binding protein (SREBP)-dependent lipogenic response to feeding, exacerbating diet-induced liver steatosis (Zhang et al. 2017). In line with these findings, Rora restoration attenuated fatty liver via activation of the AMPK and repression of the liver X-receptor alpha (LXR-alpha) (Kim et al. 2012b).