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Mouse models for multistep tumorigenesis. 总被引:3,自引:0,他引:3
The mouse is an ideal model system for studying the molecular mechanisms underlying the pathogenesis of human cancer. The generation of transgenic and gene-knockout mice has been instrumental in determining the role of major determinants in this process, such as oncogenes and tumor-suppressor genes. In the past few years, modeling cancer in the mouse has increased in its complexity, allowing in vivo dissection of the fundamental concepts underlying cooperative oncogenesis in various tumor types. In this review, we discuss how this transition has been facilitated, providing relevant examples. We also review how, in the post-genome era, novel methodologies will further accelerate the study of multi-step tumorigenesis in the mouse. 相似文献
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Engineering cancer-associated mutations into the mouse germline is an important tool for biological studies of growth control and tumorigenesis. Tractable models of many human cancers now exist in which the initiating genetic lesions have been elucidated and, in some instances, where the cooperating lesions are also known. The urgent need for more effective strategies for treating human cancer has stimulated interest in harnessing these models to test therapeutic agents. Although the ultimate value of genetically engineered mouse models for cancer drug discovery is unknown, several encouraging experiments provide proof of principle. 相似文献
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《Genomics》1995,29(3)
The BRCA1 gene is in large part responsible for hereditary human breast and ovarian cancer. Here we report the isolation of the murineBrca1homologue cDNA clones. In addition, we identified genomic P1 clones that contain most, if not all, of the mouseBrca1locus. DNA sequence analysis revealed that the mouse and human coding regions are 75% identical at the nucleotide level while the predicted amino acid identity is only 58%. A DNA sequence variant in theBrca1locus was identified and used to map this gene on a (Mus m. musculusCzech II × C57BL/KsJ)F1 × C57BL/KsJ intersubspecific backcross to distal mouse chromosome 11. The mapping of this gene to a region highly syntenic with human chromosome 17, coupled with Southern and Northern analyses, confirms that we isolated the murineBrca1homologue rather than a related RING finger gene. The isolation of the mouseBrca1homologue will facilitate the creation of mouse models for germline BRCA1 defects. 相似文献
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In this issue, Hughes-Davies et al. describe a novel gene product, EMSY, which suppresses the transactivational activity of BRCA2. EMSY is located within an amplicon in sporadic breast and ovarian cancers, suggesting that its overexpression may mimic the effects of BRCA2 inactivation. The implications for BRCA2 function are discussed. 相似文献
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The debate regarding the patenting of genes has extended into the post-genome era. With only approximately 35000 genes deduced from the draft sequence of the human genome, there are fears that a few companies have already gained monopoly on the potential benefits from this knowledge. Nevertheless, it is accepted that proteins determine gene function and function is not readily predicted from gene sequence. Furthermore, genes can encode multiple proteins and a single protein can have multiple functions. Here, we argue that unraveling the intrinsic complexity of proteins and their functions is the key towards determining the utility requirement for patenting protein inventions and consider the possible socioeconomic impact. 相似文献
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Yongjing He Zhenjun Deng Mansour Alghamdi Lechun Lu Mark W. Fear Li He 《Cell proliferation》2017,50(2)
Keloid scarring is a dermal fibroproliferative response characterized by excessive and progressive deposition of collagen; aetiology and molecular pathology underlying keloid formation and progression remain unclear. Genetic predisposition is important in the pathogenic processes of keloid formation, however, environmental factors and epigenetic mechanisms may also play pivotal roles. Epigenetic modification is a recent area of investigation in understanding the molecular pathogenesis of keloid scarring and there is increasing evidence that epigenetic changes may play a role in induction and persistent activation of fibroblasts in keloid scars. Here we have reviewed three epigenetic mechanisms: DNA methylation, histone modification and the role of non‐coding RNAs. We also review the evidence that these mechanisms may play a role in keloid formation ‐ in future, it may be possible that epigenetic markers may be used instead of prognostic or diagnostic markers here. However, there is a significant amount of work required to increase our current understanding of the role of epigenetic modification in keloid disease. 相似文献
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Jacob I. Laughner Scott B. Marrus Erik R. Zellmer Carla J. Weinheimer Matthew R. MacEwan Sophia X. Cui Jeanne M. Nerbonne Igor R. Efimov 《PloS one》2013,8(10)
Animal models have become a popular platform for the investigation of the molecular and systemic mechanisms of pathological cardiovascular physiology. Chronic pacing studies with implantable pacemakers in large animals have led to useful models of heart failure and atrial fibrillation. Unfortunately, molecular and genetic studies in these large animal models are often prohibitively expensive or not available. Conversely, the mouse is an excellent species for studying molecular mechanisms of cardiovascular disease through genetic engineering. However, the large size of available pacemakers does not lend itself to chronic pacing in mice. Here, we present the design for a novel, fully implantable wireless-powered pacemaker for mice capable of long-term (>30 days) pacing. This design is compared to a traditional battery-powered pacemaker to demonstrate critical advantages achieved through wireless inductive power transfer and control. Battery-powered and wireless-powered pacemakers were fabricated from standard electronic components in our laboratory. Mice (n = 24) were implanted with endocardial, battery-powered devices (n = 14) and epicardial, wireless-powered devices (n = 10). Wireless-powered devices were associated with reduced implant mortality and more reliable device function compared to battery-powered devices. Eight of 14 (57.1%) mice implanted with battery-powered pacemakers died following device implantation compared to 1 of 10 (10%) mice implanted with wireless-powered pacemakers. Moreover, device function was achieved for 30 days with the wireless-powered device compared to 6 days with the battery-powered device. The wireless-powered pacemaker system presented herein will allow electrophysiology studies in numerous genetically engineered mouse models as well as rapid pacing-induced heart failure and atrial arrhythmia in mice. 相似文献
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Thomas R. Insel 《Mammalian genome》2001,12(10):755-757
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Subhasis Banerjee Harpal Randeva Anne E Chambers 《Reproductive biology and endocrinology : RB&E》2009,7(1):4-6
The concept that oxidative stress contributes to the development of human preeclampsia has never been tested in genetically-defined
animal models. Homozygous deletion of catechol-O-methyl transferase (Comt-/-) in pregnant mice leads to human preeclampsia-like
symptoms (high blood pressure, albuminurea and preterm birth) resulting from extensive vasculo-endothelial pathology, primarily
at the utero-fetal interface where maternal cardiac output is dramatically increased during pregnancy. Comt converts estradiol
to 2-methoxyestradiol 2 (2ME2) which counters angiogenesis by depleting hypoxia inducible factor-1 alpha (HIF-1 alpha) at
late pregnancy. We propose that in wild type (Comt++) pregnant mice, 2ME2 destabilizes HIF-1 alpha by inhibiting mitochondrial
superoxide dismutase (MnSOD). Thus, 2ME2 acts as a pro-oxidant, disrupting redox-regulated signaling which blocks angiogenesis
in wild type (WT) animals in physiological pregnancy. Further, we suggest that a lack of this inhibition under normoxic conditions
in mutant animals (Comt-/-) stabilises HIF-1 alpha by inactivating prolyl hydroxlases (PHD). We predict that a lack of inhibition
of MnSOD, leading to persistent accumulation of HIF-1 alpha, would trigger inflammatory infiltration and endothelial damage
in mutant animals. Critical tests of this hypothesis would be to recreate preeclampsia symptoms by inducing oxidative stress
in WT animals or to ameliorate by treating mutant mice with Mn-SOD-catalase mimetics or activators of PHD. 相似文献
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《European journal of cell biology》2022,101(2):151205
Fungal extracellular vesicles (EVs) have attracted increased attention in recent years. Originated from a serendipitous discovery, the initial observation of fungal EVs resulted in a set of data repetitively rejected by several scientific journals, which raised questions about their authenticity. However, after the most fundamental experimental issues related to their observation were addressed, fungal EVs were characterized in dozens of species and became an emerging field. In this essay, we will discuss these fundamental findings and the potential of fungal EVs for the development of vaccines and antifungals. 相似文献
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From fragile X mental retardation protein to Rac1 GTPase: new insights from Fly CYFIP 总被引:6,自引:0,他引:6
Mutations in either the Rho GTPase pathway or in the fragile X mental retardation (FMR1) gene produce neuronal connectivity defects. In this issue of Neuron, Schenck et al. use biochemical and genetic approaches in Drosophila to examine the interactions between dFMR1 and dRac1 and provide evidence that the cytoplasmic FMRP interacting protein (CYFIP) links Rac-dependent cytoskeleton remodeling and dFMR1-dependent control of translation in a unique pathway to modulate neuronal morphogenesis. 相似文献