Rubinstein−Taybi Syndrome
Dongyou Liu in 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].
Gene Therapy for Retinal Disease
Glenn J. Jaffe, Paul Ashton, P. Andrew Pearson in Intraocular Drug Delivery, 2006
All of the conventional vector systems are limited to “on” expression. Attempts have been made to develop systems where the foreign gene can be turned on and off at will. Such regulatable promoters are turned on or off by the addition of a diffusible drug (such as tetracycline). The tetracycline-regulated system depends on two separate vectors, one containing a promoter-driving expression of a transcriptional activator (“transactivator”) and the other containing the regulated therapeutic transgene. After coinfection with these two vectors, the host cell contains machinery to produce the therapeutic transgene and an inducible system to turn on its expression. In its basal state, the therapeutic vector is quiescent or nearly so. The first vector produces the transactivator not normally present in the microenvironment of the host cell. The second vector carries a transgene that is not activated unless it encounters both the transactivator and tetracycline. By adding tetracycline to the system, the transactivator can bind to the promoter of the therapeutic gene, ultimately resulting in production of the therapeutic drug (Fig. 2). Of note, this inducible system can be designed in the opposite configuration, such that application of an exogenous agent can result in suppression of transgene expression. Both the tetracycline-regulated system and the rapamycin-regulated system have functioned successfully and repetitively in the retina in animal studies (44–46).
Mouse Models in Personalized Cancer Medicine
II-Jin Kim in Cancer Genetics and Genomics for Personalized Medicine, 2017
One of the limitations of CRE-mediated recombination is that it is not reversible. In general, this is not a severe shortcoming in mouse models of cancer because, unfortunately, human cancer is rarely naturally reversible. However, there are cases where oncogenic switchability is desirable, and furthermore, the ability to toggle the expression of an inhibitor is required to model periodic treatment regimes. In this context, the most common genetic tools to model the effect of a potential drug are expression of siRNA, dominant negatives or other competitors. A popular method for achieving switchability, both in vitro and in vivo, is the use of tetracycline controlled transcriptional activation (Gossen et al., 1995). In this system, addition of tetracycline (or a derivative such as doxycycline) to the drinking water of mice can trigger either expression or repression of the desired DNA sequence integrated into the mouse genome. For this to take place, the second component of the system is also transgenically inserted: rtTA or tTA, known as Tet-On and Tet-Off transactivators. These transactivator genes give versatility to the system because they can be placed under the control of a constitutive promoter such as CMV to drive their ubiquitous expression, or placed downstream of a tissue specific promoter to trigger expression only in certain tissues.
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].
Emerging therapeutics in Huntington’s disease
Published in Expert Opinion on Emerging Drugs, 2021
Robert Wiggins, Andrew Feigin
Early evidence that disease modifying therapies aimed at the genetic cause of HD could alter the disease course has come from the use of transgenic HD mouse models with conditional expression. This was achieved using a tetracycline-regulated transactivator which controls transcription of the mutant gene. When tetracycline is introduced into the system, it binds to the transactivator and transcription is downregulated. When expression is not inhibited, this transgenic HD mouse model demonstrates motor dysfunction reminiscent of HD accompanied by pathological changes including decreased brain and striatal size, ventricular enlargement, neuronal inclusions, reactive astrocytosis, and decreased D1 receptor levels. After 18 weeks of gene expression (no doxycycline, gene-on), a sufficient time for motor dysfunction and neuropathologic changes to become evident, doxycycline was introduced, turning of gene expression. This reversed many of the pathological findings including decreased levels of nuclear htt in the striatum and cortex, disappearance of intra- and extranuclear aggregates, greater brain volumes, and reduction in reactive astrocytes. The declining D1 receptor levels seen in gene-on mice plateaued in the gene-off mice. Additionally, motor function improved in the gene-off mice. This early study suggested that continuous mutant gene expression may be required for the ongoing motor and neuropathologic phenotype of HD to manifest, raising hope that if expression of the mutant huntingtin gene could be inhibited, the pathology of HD along with its symptoms could be halted or even reversed [7].
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.
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