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Rubinstein−Taybi Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The CREBBP gene on chromosome 16p13.3 comprises 31 transcribed exons spanning 154 kb. The 3-prime distal flanking region of the CREBBP gene contains the DNASE1 and TRAP1 (or HSP75) genes. The CREBBP gene encodes a 2442 aa nuclear transcriptional coactivator protein (CREBBP) of 265 kDa, which includes a central region (consisting of a bromodomain and a histone acetyltransferase [HAT] domain) flanked by two transactivation domains. While the bromodomain facilitates protein−protein interactions, the HAT domain demonstrates intrinsic histone acetyltransferase activity, which plays a vital role in the regulation of gene expression through acetylation of histones H3 and H4, de-condensing chromatin and allowing for transcription. In addition, the transactivation domains recruit and interact with transcriptional machinery such as RNA polymerase II (Pol II) complex, co-activators, and repressors. Through these functionally distinct domains, CREBBP acts as a mediator of different signaling pathways, a negative regulator of the cell cycle by repressing the transition from G1 to S phase, and also a scaffold to stabilize additional protein interactions with the transcription complex via chromatin remodeling [1].
Melanoma Growth Stimulatory Activity: Physiology, Biology, Structure/Function, and Role in Disease
Published in Richard Horuk, Chemoattractant Ligands and Their Receptors, 2020
Ann Richmond, Rebecca L. Shattuck
While these studies have been carried out in vitro, there is some information suggesting that the NF-kB element is a key regulator of transactivation of this family of genes in vivo. Using an in vivo lung model, Blackwell et al. demonstrated that they can correlate activation of NF-kB in the nuclear extracts from lung lavage cells with the increases in CINC mRNA levels.137 They have shown that NF-kB in the lung is activated by endotoxemia and that activation is associated with expression of CINC mRNA, production of biologically active CINC, and the development of neutrophilic lung inflammation. Furthermore, they have shown that activation of NF-kB and the development of acute inflammatory lung injury can be blocked by treatment with the antioxidant N-acetyleysteine (Christman, unpublished results).
Gene Therapy
Published in Danilo D. Lasic, LIPOSOMES in GENE DELIVERY, 2019
Several thousand diseases can be traced to defective or missing functional genes, and it is hoped that by delivering the appropriate gene into the appropriate cells, the mutated or missing proteins can be synthesized and the signs of the disease alleviated. In the majority of cases the mutation is in the coding region of the gene. This can result in an amino acid substitution, and if this happens in an important domain of the protein, it may not be functional. On the other hand, mutations in the regulatory regions or in the DNA-binding or transactivation domains of transcription factors normally result in downregulation of gene expression.
Trypsinogen and chymotrypsinogen: potent anti-tumor agents
Published in Expert Opinion on Biological Therapy, 2021
Aitor González-Titos, Pablo Hernández-Camarero, Shivan Barungi, Juan Antonio Marchal, Julian Kenyon, Macarena Perán
Finally, both PAR1 and PAR2 can transactivate other surface receptors. ‘Transactivation’ is defined as the activation of a second type of surface membrane receptor by the previous activation of a first one, in a mechanism which does not imply any transcription or translation processes [101]. To note, it has been pointed out that there is an importance of the transactivation of tyrosin kinase receptors by G protein-coupled receptors, like PARs, which enables G protein coupled receptors to signal even through cellular growth pathways [102]. Importantly, the transactivation of the epidermal growth factor receptor by both PAR1 [103,104] and PAR2 [105,106] has been reported. This is a very relevant fact since it has also been shown that the EGF pathway can promote the alternative splicing of RAC1 leading to the synthesis of RAC1β [107], which has been suggested to be a key factor responsible for the anti-tumor properties of pancreatic (pro)enzymes [48].
Glucocorticoids in rheumatoid arthritis: the silent companion in the therapeutic strategy
Published in Expert Review of Clinical Pharmacology, 2020
Onorina Berardicurti, Piero Ruscitti, Viktoriya Pavlych, Alessandro Conforti, Roberto Giacomelli, Paola Cipriani
As above mentioned, the transrepression effects are mainly responsible for the anti-inflammatory and immunosuppressive effects of GCs. On these bases, selective GR ligands, such as selective GR agonists (SEGRAs) and the dissociated agonists of the GCs receptor (DAGRs), have been developed, to optimize GCs therapies. The proposed mechanism of action is the induction of GCs therapeutic activity via the transrepression-mediated GCs effects. In fact, transrepression effects are main responsible for GCs anti-inflammatory and immunomodulating properties. On the contrary, other actions are mediated by transactivation effects, the latter associated with frequent occurring side effects [66,67]. At present, although conclusive data concerning selective GR ligands efficacy are still missing, a longitudinal dose–response analysis to identify the efficacy of the DAGR PF-04171327 was performed [68]. In this work analyzing data from a phase II, RCT, the reduction of the disease activity was similar in patients treated with PF-04171327 when compared to oral GCs-treated patients [69,70].
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 addition to the variable response observed in tumors, another main problem of glucocorticoid clinical use is the occurrence of adverse effects, that can often be severe. Side effects concern in particular metabolic regulation and are believed to be linked mainly to the transactivating actions of these agents, while the immunosuppressive and anti-inflammatory effects seem to be related to the transrepressive activity. For this reason, many efforts are currently aimed at dissociating therapeutic efficacy, related to transrepression, from metabolic side effects, more connected to transactivation. In recent years, a number of selective glucocorticoid receptor modulators (SGRMs) have been developed and compounds that exert a more specific effect when bound to the glucocorticoid receptor have been obtained [13–15]; some of these SGRMs have been also evaluated in different tumors [16]. So far, none of these molecules have been translated into the clinics, but research on this topic is ongoing and is quite active. The present review will discuss recent findings in the field of novel selective glucocorticoid modulators to be used in anticancer therapy, focusing on the patent literature from 2014 to present.