International symposium: Applications of Genetic Engineering in Pediatric Medicine. Oct. 15-16, 1986, 1986, Tokyo, Japan. Proceedings.
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Breast cancer is a multifactorial disease that develops as a result of interactions among genetic, environmental, and hormonal factors. Multiple genetic derangements are believed to be involved in the pathogenesis of breast cancer, including the inactivation of tumor suppressor genes and/or the disregulation of proto-oncogenes. Age, hormones, and environmental factors further influence these genetic derangements. Spontaneous and chemically induced animal models of breast cancer have been limited in their usefulness. The advent of targeted gene mutations has allowed for a more specific exploration of the pathogenesis of breast cancer by creating mouse models that mimic single or multiple gene alterations found in human mammary tumors. The genes targeted in these models include mouse mammary tumor integration sites and genes that encode for growth regulators, signal transduction proteins, cell cycle proteins, and cell matrix proteinases. In this review, I summarize tumor morphology and the relevance of each model to the pathogenesis and progression of human breast cancer. These models have great potential for elucidating the multistep process of mammary gland carcinogenesis and for contributing to the identification of novel therapeutic targets.
As a proof of concept, the qualitative and quantitative engineering of carotenoid formation has been achieved in crop plants. Successful reports in tomato, potato, rice, and canola all describe the enhancement of carotenoid with nutritional value, while in model systems such as tobacco and Arabidopsis the engineering of carotenoid to confer abiotic stress has been described. For all the successful applications there have been many examples of unintended/unpredicted phenotypes and results. Typically this has resided from our lack of understanding of carotenoid formation and its regulation. In the present article, we will review advances in carotenoid formation and its regulation to illustrate how metabolic engineering experiments have shed light on regulatory mechanisms.
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Transgenic tobacco and eggplants expressing the coding region of the iaaM gene from Pseudomonas syringae pv. savastanoi, under the control of the regulatory sequences of the ovule-specific DefH9 gene from Antirrhinum majus, showed parthenocarpic fruit development. Expression of the DefH9-iaaM chimeric transgene occurs during flower development in both tobacco and eggplant. Seedless fruits were produced by emasculated flowers. When pollinated, the parthenocarpic plants produced fruits containing seeds. In eggplant, the genetic manipulation allowed fruit set and growth under environmental conditions prohibitive for fruit setting in the untransformed line, which did not set fruit at all. Under normal environmental conditions, production of marketable fruits took place from pollinated and unpollinated transgenic flowers, while flowers of untransformed control plants did produce fruits of marketable size only from fertilized flowers.
Most microorganisms do not produce sialic acid (sialate), and those that do appear to use a biosynthetic mechanism distinct from mammals. Genetic hybrids of nonpathogenic, sialate-negative laboratory Escherichia coli K-12 strains designed for the de novo synthesis of the polysialic acid capsule from E. coli K1 proved useful in elucidating the genetics and biochemistry of capsule biosynthesis. In this article we propose a dynamic model of sialometabolism to investigate the effects of biosynthetic neu (N-acetylneuraminic acid) and catabolic nan (N-acylneuraminate) mutations on the flux of intermediates through the sialate synthetic pathway. Intracellular sialate concentrations were determined by high pH anion exchange chromatography with pulsed amperometric detection. The results indicated that a strain carrying a null defect in the gene encoding polysialyltransferase (neuS) accumulated > 50 times more CMP-sialic acid than the wild type when strains were grown in a minimal medium supplemented with glucose and casamino acids. Metabolic accumulation of CMP-sialic acid depended on a functional sialic acid synthase (neuB), as shown by the inability of a strain lacking this enzyme to accumulate a detectable endogenous sialate pool. The neuB mutant concentrated trace sialate from the medium, indicating its potential value for quantitative analysis of free sialic acids in complex biological samples. The function of the sialate aldolase (encoded by nanA) in limiting intermediate flux through the synthetic pathway was determined by analyzing free sialate accumulation in neuA (CMP-sialic acid synthetase) nanA double mutants. The combined results demonstrate how E. coli avoids a futile cycle in which biosynthetic sialate induces the system for its own degradation and indicate the feasibility of generating sialooligosaccharide precursors through targeted manipulation of sialate metabolism.
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