PML/RARα Fusion Gene and Response to Retinoic Acid and Arsenic Trioxide Treatment
Sherry X. Yang, Janet E. Dancey in Handbook of Therapeutic Biomarkers in Cancer, 2021
PML/RARa behaves as a potent repressor of the RA signalling pathway (Fig. 10.1). The traditional model postulated that PML/RARa acted as a constitutive transcriptional repressor that altered the normal RARa signalling in APL cells, as the chimeric protein is unable to respond to physiological fluctuations of RA [42]. The transcriptional repression was shown to be the consequence of greatly enhanced binding to the SMRT/NCoR co-repressors and HDACs [23]. PML/RARa homodimerises and binds to DNA at the RARE sites even in the absence of its normal heterodimeric partner RXR. The homodimerisation is thought to enhance the binding of the physiological RARa interactors. Simplistically, enhanced corepressors binding depends upon the fact that the homodimer harbours two co-repressor docking sites and not just one as in RXR/RARa heterodimer, leading to a change in stoichiometry of association of PML/RARa with co-repressors and chromatin modifiers [39]. However, in addition, the formation of homodimers leads to the creation of novel binding interfaces. Histone methyltransferase SUV39H1, responsible for trimethylation of lysine 9 of histone H3 is one of the chimera-specific partners responsible for imposing a heterochromatin-like structure on target genes, thereby establishing permanent transcriptional silencing [9]. Similarly, polycomb repressive complex 2 (PRC2) represents another example of a new PML/RARa interactor. It has been found that PRC2 is recruited to tumour suppressor genes causing and maintaining their silencing during the initial steps of PML/RARa driven leukaemogenesis [57].
Differentiation Induction in Acute Promyelocytic Leukemia
Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey in Innovative Leukemia and Lymphoma Therapy, 2019
Retinoic acid (RA) is important in embryonic development and in a variety of cellular processes. The activity of RA is mediated by RAR that are part of the nuclear receptor superfamily. Several RARs have been described including RXR, RARα, RARβ, and RARγ. RA activates RARα to bind to RAR elements (RARE) located in the promoter region of genes important for differentiation such as those of RARα, RARβ, and RARγ, and RXR. A heterodimer of RARα and RXR forms and in conjunction with other coactivator proteins binds to DNA and stimulates transcription through two domains. The ligand-independent domain (AF-1) forms on the N-terminal of the protein and works in a promoter context-dependent manner (5,7,8). The ligand-dependent domain (AF-2) is associated with the compressors NCoR, SMRT, Sin3A, and histone deacetylase. Ligand binding to the AF-2 domain releases these corepressors and allows for transcription of the target genes (5,9–11).
Molecular diagnosis of endometriosis
Carlos Simón, Linda C. Giudice in The Endometrial Factor, 2017
Nuclear receptor regulation of transcription requires the action of nuclear coregulators that enhance (coactivator) (NCOAs) or repress (corepressor) (NCORs) transcriptional activity (65,66). Tissue and cell-type differences in coregulator expression, and hence posttranslational modification, likely contribute to cell specificity of steroid hormone action (65). The nuclear receptors interact with DNA-methylating or -demethylating enzymes and histone-modifying enzymes in the transcriptional complex, and histone modification and DNA methylation are interconnected in regulating gene expression and chromatin remodeling (67). Endometrium being a steroid hormone-responsive tissue is heavily dependent on nuclear ER and PR interaction with coregulators, resulting in cyclic changes in cellular processes, including proliferation, apoptosis, differentiation, and angiogenesis. As discussed above, decreased expression of PRs and hypermethylation of the PGRB promoter in women with endometriosis have been reported (32,50). Aberrant levels of nuclear receptors and their coregulators in ectopic endometriotic lesions have been implicated in the progression of endometriosis (reviewed in (68)). In the setting of endometriosis, our group found increased expression of NCOR1 in secretory phase eutopic endometrium, most likely downregulating genes targeted by P4 (60), while increased NCOA1 in both proliferative endometrium (PE) and early secretory endometrium (ESE) from women with endometriosis warrants further investigation (Figure 4.2).
MicroRNA-27b-3p inhibits apoptosis of chondrocyte in rheumatoid arthritis by targeting HIPK2
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2019
Yizhao Zhou, Sihong Li, Ping Chen, Benyu Yang, Junjun Yang, Renfeng Liu, Jiamiao Li, Duo Xia
Homeodomain-interacting protein kinase (HIPK2) is a member of the homeodomain-interacting protein kinase family, which is able to interact with homeodomain transcription factors and many other transcription factors like p53. It is also able to function as either corepressor or coactivator. HIPK2 is also able to regulate a wide range of biological processes, including cell proliferation, tumorigenesis, vasculogenesis, DNA damage response, apoptosis, tissue fibrosis, epithelial-mesenchymal transition and neural development [27,28]. Additionally, HIPK2 is also reported to participate in various diseases like tumor progression and fibrosis of pulmonary [29]. HIPK2 is also reported to induce cell cycle arrest and apoptosis in response to genotoxic damage [30,31]. Moreover, the down-expression of HIPK2 also impairs the pro-apoptosis ability and induces drug resistance [32]. The role of HIPK2 in RA has not been researched in detail ever, a previous study using whole-exome sequencing technique demonstrated variants of gene HIPK2 may induce functional impact on RA pathogenesis [33]. Therefore, it is the first time to investigate the functional effects of HIPK2 protein, as well as the upstream regulator (miR-27b-3p), in RA development. This study might provide a potential therapeutic target for RA treatment in the clinic.
FEVR phenotype associated with septo-optic dysplasia
Published in Ophthalmic Genetics, 2019
David L. Zhang, Michael P. Blair, Janice L. Zeid, Syeda S.T. Basith, Michael J. Shapiro
Whole exome sequencing did identify two variants of uncertain significance: (1) A D1198A variant in the BCORL1 gene; and (2) a M124V variant in the POU1F1 gene. Shuurs-Hoeijmakers et al. found that BCORL1, a transcriptional corepressor, is expressed in brain and neuronal tissue and may play a role in brain development (17). However, due to a lack of empirical findings, this particular variant has not been classified as benign or pathogenic. POU1F1 codes for a transcription factor needed for pituitary development and is expressed in the anterior pituitary (18). This mutation was classified as a variant of uncertain significance by the genetic testing facility due to a lack of previous evidence of causality. The mutation was expected to be fully penetrant but did not lead to any symptoms in the father, who was heterozygous. However, based on the clinical findings, it is possible that the variant may play a role in the pituitary symptoms observed and that the father may be non-expressive for epigenetic reasons. Both of these variants of uncertain significance are intriguing, and one may imagine a potential contribution to the clinical features observed in this case. It is also conceivable that intron mutations may play a role in pathogenesis.
Fabrication and characterization of solid lipid nano-formulation of astraxanthin against DMBA-induced breast cancer via Nrf-2-Keap1 and NF-kB and mTOR/Maf-1/PTEN pathway
Published in Drug Delivery, 2019
Tao Sun, Jun Gao, Dan Han, Hongyan Shi, Xianqiang Liu
After origination of carcinogenesis, cancer cells divide and propagate in a number of new cells resulting in an increase in the massive tumor burden (Darlington, 1948). Fast-growing neoplastic cells start the alteration of numerous metabolic pathways, involved in the lipogenesis and other energy regulation, to complete the basic requirement for proliferation (Raulet & Guerra, 2009; Vincent et al., 2013). Research suggests that the LXR plays a crucial role in the physiological regulation of carbohydrate metabolism and lipid maintenance, and also suggest that the activation of LXR altered the progression of cancer cell (Xu et al., 2005; Korach-Andre et al., 2011). The researcher suggests that the LXR agonists have been extensively studied to restore the modulation of inflammatory pathway, lipogenic, and metabolic alteration in the proliferation of cancerous condition (Korach-Andre et al., 2011; Korach-André et al., 2011). The researchers target the LXR for the conformational changes that induce the co-activator for corepressor complex exchange and target genes transcription. Researchers also suggest that the LXR activation suppresses the pro-inflammatory cytokines which do not contain the LXR response elements (LXREs), a phenomenon referred as trans repression, and also regulates the intestinal cholesterol absorption via various transporters (Xu et al., 2005; Korach-Andre et al., 2011; Korach-André et al., 2011).