Mouse As4.1 cells, obtained after transgene-targeted oncogenesis to induce neoplasia in renal renin-expressing cells, express high levels of renin mRNA from the endogenous Ren-1(c) gene. We have used these cells to characterize the role of the Ren-1(c) proximal promoter (+6 to -117) in the regulation of renin gene transcription. It was found that 4.1 kilobases (kb) of Ren-1(c) 5'-flanking sequence, in combination with the proximal promoter, are required for strong activation (approximately 2 orders of magnitude over the basal level of the promoter alone) of the chloramphenicol acetyltransferase reporter in transfection assays. Within the 4.1-kb fragment, a 241-base pair region was identified that retains full activity in an orientation-independent manner in combination with the promoter. The resulting transcripts initiate at the normal renin start site. Electrophoretic mobility shift assays identified a sequence at approximately position -60 in the promoter region that binds nuclear proteins specific for renin-expressing As4.1 cells. Mutations in this sequence, which disrupt binding of nuclear protein(s), completely abolish activation of transcription by the 4. 1-kb fragment. Activation of transcription by the 241-base pair enhancer was still observed, although it was diminished in magnitude (60-fold over the mutated promoter alone). We present a model derived from the current data that suggests that regulation of renin expression is achieved through cooperation of transcription factors binding at the proximal promoter element and a distal enhancer element to abrogate or override the effects of an intervening negative regulatory region.
Catalogue of somatic mutations in cancerContinuing with the cancer theme, even a brief examination of COSMIC -Catalogue of somatic mutations in cancer [1] shows the weight PTC mutations carry in the causation of a whole range of cancers through TS inactivation. As such, COSMIC provides for an excellent AbstractThe burden of inherited diseases in terms of congenital defects and cancer predisposition in addition to a multitude of neurological, cardiovascular and other organ diseases arising sporadically during life is enormous on the individual, immediate family and society globally. I approach this major burden to human society by invoking the powerful technology behind read-through, whereby disease-causing substitution nonsense mutations, oftentimes at the root of human diseases, are rescued. Further, the importance of nonsense mutations in the realm of developmental factors linked to cancer stem cell maintenance is presented. The methodology behind the technique is given and proof of concept behind its use ex vivo and in clinical trials. The discovery of a novel read-through drug, Amlexanox, which has been in use for over twenty years in dentistry for oral ulcerations, represents a next generation read-through agent. This agent has been demonstrated in cell lines to correct functional loss in cystic fibrosis CFTR, dystrophin and the tumour suppressor, p53. Its novel ability to inhibit nonsense mediated decay is discussed. Amlexanox is therefore presently ready for testing in a wide variety of in vivo models of human diseases and also in clinical trials. Given the safety profile of Amlexanox and ex vivo efficacy in studies thus far it is envisaged that this accepted medication shall successfully debut as an all-purpose agent for the prevention and management of human diseases.
In the present review I propose a novel model system to analyze and to aid prediction of suitable targeted treatments aimed at therapy-resistant cancer cells. The concept of cancer cell prosurvival reaction to adverse external tumor microenvironment is explored in the context of the reaction of myocardium to unfavorable physiologic conditions. Many of the protective and indeed nonprotective (tumor suppressor) reactive mechanisms in both cancer and heart tissue challenged with an adverse environment follow similar and predictable patterns. Based on these observations, a model is constructed that may aid prediction of future therapies aimed to target cancer--particularly chemotherapy/radiotherapy resistance and dormant disease. As another feature of the model, ways to better forecast future therapies aimed at augmenting cardioprotective paths is made possible through understanding of pathways used to sustain cancer cells under external challenges.
Nonsense mutations, which lead to premature termination codons, are prevalent in a wide variety of cancers and many studies highlight clear evidence of functions. Based on these observations, a strategy is proposed for using various natural and synthetic derivatives based on aminoglycosides and their conjugates that have the unique property of read-through of nonsense mutations. The results and current status of this group of drugs are presented to show their effectiveness in treating other nonsense-codon-mediated diseases unrelated to cancer such as cystic fibrosis, thalassaemia, and muscular dystrophy. Concluding remarks indicate that this novel approach to cancer treatment with relatively low toxicity and reversibility of drug action as well as potential good patient acceptance and compliance ought to be now trialed for use in treating a wide variety of cancers.
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