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Naturally Occurring Histone Deacetylase (HDAC) Inhibitors in the Treatment of Cancers
Published in Namrita Lall, Medicinal Plants for Cosmetics, Health and Diseases, 2022
Sujatha Puttalingaiah, Murthy V. Greeshma, Mahadevaswamy G. Kuruburu, Venugopal R. Bovilla, SubbaRao V. Madhunapantula
Several studies have demonstrated that protein–protein interactions control the expression of HDACs through: (a) alternative RNA splicing; (b) the modulation of the availability of cofactors; (c) varied subcellular localization; and (d) different degrees of proteolytic processing (Gallinari et al., 2007; Seto and Yoshida, 2014). Individual HDAC proteins, especially HDAC1 and HDAC2, are generally low in enzyme activity; however, when associated with protein complexes such as Sin3, nucleosome remodeling and deacetylase (NuRD), and co-repressor for element-1-silencing transcription factor (CoREST), they exhibit enhanced function, indicating the importance of protein–protein interactions in controlling their biological activity (Banks et al., 2018).
Endocrine Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
In humans, the two forms of the estrogen receptor are encoded by different genes, ESR1 and ESR2 on the sixth and fourteenth chromosome (6q25.1 and 14q23.2), respectively. Due to alternative RNA splicing, several ER isoforms are also known to exist. Both ERs are widely expressed in different tissue types, although there are some notable differences in their expression patterns. For example, ERα is found predominantly in the endometrium, ovarian stromal cells, the hypothalamus, and in breast cancer cells. It is also found in the epithelium of the efferent ducts in the testes of men. The ERβ protein has been documented in the lungs, intestinal mucosa, prostate, kidney, brain, bone, and heart, and in ovarian granulosa and endothelial cells. To date, at least three ERα and five ERβ isoforms have been identified, some of which have specific functions. For example, the ERβ isoform subtypes can only transactivate transcription when a heterodimer with the functional ERß1 receptor of 59 kDa is formed, and the ERß3 receptor has been detected at high levels in the testes.
Enzymes
Published in Stephen W. Carmichael, Susan L. Stoddard, The Adrenal Medulla 1986 - 1988, 2017
Stephen W. Carmichael, Susan L. Stoddard
Human TH cDNA was isolated by molecular cloning by Kaneda, Kobayashi, Ichinose et al. (1987). They found a novel type of cDNA clone whose NH2-terminal sequence is similar to but really distinct from that of each of the three types of TH cDNA previously reported. Southern blot analysis of human genomic DNA indicated that TH is encoded by a single gene. This suggests that the four different forms of TH mRNA are produced by alternative RNA splicing from a single primary transcript.
Exploiting differential RNA splicing patterns: a potential new group of therapeutic targets in cancer
Published in Expert Opinion on Therapeutic Targets, 2018
Nidhi Jyotsana, Michael Heuser
The ‘one gene-one enzyme’ theory by Beadle and Tatum has been significantly reformed due to the frequently reported occurrence of alternative RNA splicing. In addition to alternative splicing, alternative promoter usage, alternative polyadenylation sites, and RNA editing may enhance transcriptome diversity. The different splicing events of a single gene may result in different kinds of mRNAs, shifting the central dogma to the current understanding that one gene gives rise to several RNAs via alternative splicing, resulting in multiple proteins.
Colorectal cancer screening and diagnosis: omics-based technologies for development of a non-invasive blood-based method
Published in Expert Review of Anticancer Therapy, 2021
María Gallardo-Gómez, Loretta De Chiara, Paula Álvarez-Chaver, Joaquin Cubiella
RNA-seq has enabled identification of new non-coding RNAs, gene fusions, gene isoforms, in addition to quantification of alternative RNA-splicing events. Furthermore, mutations in transcription factor binding sites and promoter regions, as well as aberrant methylation, can also be deduced by performing thorough analyses of RNA-seq data [40]. Integration of RNA-seq and WGS facilitates identification of RNA-editing events, which enables discovery of causative DNA variants that could be useful for CRC diagnosis.
A patent review of anticancer glucocorticoid receptor modulators (2014-present)
Published in Expert Opinion on Therapeutic Patents, 2020
Marianna Lucafò, Martina Franzin, Giuliana Decorti, Gabriele Stocco
In the absence of the ligand, the GR stands in the cytoplasm complexed with chaperone and co-chaperone proteins such as heat shock proteins, immunophillins, and others; the complex increases the affinity for the ligand and prevents GR degradation [19,30] and is also essential for nuclear translocation and subsequent transactivation [31]. Indeed, after binding, the GR undergoes conformational changes and exposes nuclear translocation signals [32], binding to nucleoporin and importins that are involved in the transport of the GR into the nucleus [33,34]. Several GRs have been described, that result from alternative RNA splicing and from translation initiation at alternative sites. The active isoform, that binds natural and synthetic glucocorticoids, is the GRα, while GRβ, a truncated variant lacking 35 amino acids at the C terminus, is unable to bind glucocorticoids and to activate gene transcription, and has a dominant-negative action on the GRα isoform [35,36]. In addition, various polymorphisms in the human GR have been described and have been related to variations in glucocorticoid binding and to differences in response to these hormones [30]. After binding the glucocorticoid, the GR undergoes a conformational change and dissociates from chaperone proteins, enters the nucleus and acts as a ligand-activated transcription factor. The GR indeed has a transactivation domain at the N-terminal part (NTD), a central zinc finger DNA binding domain (DBD) and a ligand-specific binding domain (LBD) at the C-terminus [30,37]. The activated GR binds as a homodimer, through its zinc finger domain, to the glucocorticoid responsive elements (GREs) in the promoter of glucocorticoids responsive genes and exerts its transactivating function. In addition, the GR, as a monomer, can bind to half sites with an AGAACA consensus sequence [38]. The GR can also act, as a monomer, through binding to other transcription factors through tethering or by binding to composite elements [39,40]. Recent data have shown that the GR can also bind to DNA as a tetramer [41,42]; however, it is not clear yet how the tetramer can act on transcription. In addition, the GR can induce transrepression by binding to inverted repeat GR binding sequences [43,44], leading to inhibition of gene expression. Transrepression can also be induced by indirect binding or tethering and the GR interacts with transcription factors bound to the DNA [45]. Another mechanism for transrepression occurs when the GR competes with transcription factors for DNA binding sites [46,47].