排序方式: 共有39条查询结果,搜索用时 15 毫秒
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Kai Song Hao Wu H. N. Ashiqur Rahman Yunzhou Dong Aiyun Wen Megan L. Brophy Scott Wong Sukyoung Kwak Diane R. Bielenberg Hong Chen 《Cellular and molecular life sciences : CMLS》2017,74(3):393-398
VEGF-driven tumor angiogenesis has been validated as a central target in several tumor types deserving of continuous and further considerations to improve the efficacy and selectivity of the current therapeutic paradigms. Epsins, a family of endocytic clathrin adaptors, have been implicated in regulating endothelial cell VEGFR2 signaling, where its inactivation leads to nonproductive leaky neo-angiogenesis and, therefore, impedes tumor development and progression. Targeting endothelial epsins is of special significance due to its lack of affecting other angiogenic-signaling pathways or disrupting normal quiescent vessels, suggesting a selective modulation of tumor angiogenesis. This review highlights seminal findings on the critical role of endothelial epsins in tumor angiogenesis and their underlying molecular events, as well as strategies to prohibit the normal function of endogenous endothelial epsins that capitalize on these newly understood mechanisms. 相似文献
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Cross-talk and decision making in MAP kinase pathways 总被引:1,自引:0,他引:1
Cells must respond specifically to different environmental stimuli in order to survive. The signal transduction pathways involved in sensing these stimuli often share the same or homologous proteins. Despite potential cross-wiring, cells show specificity of response. We show, through modeling, that the physiological response of such pathways exposed to simultaneous and temporally ordered inputs can demonstrate system-level mechanisms by which pathways achieve specificity. We apply these results to the hyperosmolar and pheromone mitogen-activated protein (MAP) kinase pathways in the yeast Saccharomyces cerevisiae. These two pathways specifically sense osmolar and pheromone signals, despite sharing a MAPKKK, Ste11, and having homologous MAPKs (Fus3 and Hog1). We show that in a single cell, the pathways are bistable over a range of inputs, and the cell responds to only one stimulus even when exposed to both. Our results imply that these pathways achieve specificity by filtering out spurious cross-talk through mutual inhibition. The variability between cells allows for heterogeneity of the decisions. 相似文献
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The prevention and treatment of malaria is heavily dependent on antimalarial drugs. However, beginning with the emergence of chloroquine (CQ)-resistant Plasmodium falciparum parasites 50 years ago, efforts to control the disease have been thwarted by failed or failing drugs. Mutations in the parasite's 'chloroquine resistance transporter' (PfCRT) are the primary cause of CQ resistance. Furthermore, changes in PfCRT (and in several other transport proteins) are associated with decreases or increases in the parasite's susceptibility to a number of other antimalarial drugs. Here, we review recent advances in our understanding of CQ resistance and discuss these in the broader context of the parasite's susceptibilities to other quinolines and related drugs. We suggest that PfCRT can be viewed both as a 'multidrug-resistance carrier' and as a drug target, and that the quinoline-resistance mechanism is a potential 'Achilles' heel' of the parasite. We examine a number of the antimalarial strategies currently undergoing development that are designed to exploit the resistance mechanism, including relatively simple measures, such as alternative CQ dosages, as well as new drugs that either circumvent the resistance mechanism or target it directly. 相似文献
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George RE Sanda T Hanna M Fröhling S Luther W Zhang J Ahn Y Zhou W London WB McGrady P Xue L Zozulya S Gregor VE Webb TR Gray NS Gilliland DG Diller L Greulich H Morris SW Meyerson M Look AT 《Nature》2008,455(7215):975-978
Neuroblastoma, an embryonal tumour of the peripheral sympathetic nervous system, accounts for approximately 15% of all deaths due to childhood cancer. High-risk neuroblastomas are rapidly progressive; even with intensive myeloablative chemotherapy, relapse is common and almost uniformly fatal. Here we report the detection of previously unknown mutations in the ALK gene, which encodes a receptor tyrosine kinase, in 8% of primary neuroblastomas. Five non-synonymous sequence variations were identified in the kinase domain of ALK, of which three were somatic and two were germ line. The most frequent mutation, F1174L, was also identified in three different neuroblastoma cell lines. ALK complementary DNAs encoding the F1174L and R1275Q variants, but not the wild-type ALK cDNA, transformed interleukin-3-dependent murine haematopoietic Ba/F3 cells to cytokine-independent growth. Ba/F3 cells expressing these mutations were sensitive to the small-molecule inhibitor of ALK, TAE684 (ref. 4). Furthermore, two human neuroblastoma cell lines harbouring the F1174L mutation were also sensitive to the inhibitor. Cytotoxicity was associated with increased amounts of apoptosis as measured by TdT-mediated dUTP nick end labelling (TUNEL). Short hairpin RNA (shRNA)-mediated knockdown of ALK expression in neuroblastoma cell lines with the F1174L mutation also resulted in apoptosis and impaired cell proliferation. Thus, activating alleles of the ALK receptor tyrosine kinase are present in primary neuroblastoma tumours and in established neuroblastoma cell lines, and confer sensitivity to ALK inhibition with small molecules, providing a molecular rationale for targeted therapy of this disease. 相似文献
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Weir BA Woo MS Getz G Perner S Ding L Beroukhim R Lin WM Province MA Kraja A Johnson LA Shah K Sato M Thomas RK Barletta JA Borecki IB Broderick S Chang AC Chiang DY Chirieac LR Cho J Fujii Y Gazdar AF Giordano T Greulich H Hanna M Johnson BE Kris MG Lash A Lin L Lindeman N Mardis ER McPherson JD Minna JD Morgan MB Nadel M Orringer MB Osborne JR Ozenberger B Ramos AH Robinson J Roth JA Rusch V Sasaki H Shepherd F Sougnez C Spitz MR Tsao MS Twomey D Verhaak RG Weinstock GM Wheeler DA Winckler W 《Nature》2007,450(7171):893-898
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A general integrative model for scaling plant growth, carbon flux, and functional trait spectra 总被引:1,自引:0,他引:1
Linking functional traits to plant growth is critical for scaling attributes of organisms to the dynamics of ecosystems and for understanding how selection shapes integrated botanical phenotypes. However, a general mechanistic theory showing how traits specifically influence carbon and biomass flux within and across plants is needed. Building on foundational work on relative growth rate, recent work on functional trait spectra, and metabolic scaling theory, here we derive a generalized trait-based model of plant growth. In agreement with a wide variety of empirical data, our model uniquely predicts how key functional traits interact to regulate variation in relative growth rate, the allometric growth normalizations for both angiosperms and gymnosperms, and the quantitative form of several functional trait spectra relationships. The model also provides a general quantitative framework to incorporate additional leaf-level trait scaling relationships and hence to unite functional trait spectra with theories of relative growth rate, and metabolic scaling. We apply the model to calculate carbon use efficiency. This often ignored trait, which may influence variation in relative growth rate, appears to vary directionally across geographic gradients. Together, our results show how both quantitative plant traits and the geometry of vascular transport networks can be merged into a common scaling theory. Our model provides a framework for predicting not only how traits covary within an integrated allometric phenotype but also how trait variation mechanistically influences plant growth and carbon flux within and across diverse ecosystems. 相似文献