共查询到20条相似文献,搜索用时 15 毫秒
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Sancak Y Peterson TR Shaul YD Lindquist RA Thoreen CC Bar-Peled L Sabatini DM 《Science (New York, N.Y.)》2008,320(5882):1496-1501
The multiprotein mTORC1 protein kinase complex is the central component of a pathway that promotes growth in response to insulin, energy levels, and amino acids and is deregulated in common cancers. We find that the Rag proteins--a family of four related small guanosine triphosphatases (GTPases)--interact with mTORC1 in an amino acid-sensitive manner and are necessary for the activation of the mTORC1 pathway by amino acids. A Rag mutant that is constitutively bound to guanosine triphosphate interacted strongly with mTORC1, and its expression within cells made the mTORC1 pathway resistant to amino acid deprivation. Conversely, expression of a guanosine diphosphate-bound Rag mutant prevented stimulation of mTORC1 by amino acids. The Rag proteins do not directly stimulate the kinase activity of mTORC1, but, like amino acids, promote the intracellular localization of mTOR to a compartment that also contains its activator Rheb. 相似文献
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Lin SY Li TY Liu Q Zhang C Li X Chen Y Zhang SM Lian G Liu Q Ruan K Wang Z Zhang CS Chien KY Wu J Li Q Han J Lin SC 《Science (New York, N.Y.)》2012,336(6080):477-481
In metazoans, cells depend on extracellular growth factors for energy homeostasis. We found that glycogen synthase kinase-3 (GSK3), when deinhibited by default in cells deprived of growth factors, activates acetyltransferase TIP60 through phosphorylating TIP60-Ser(86), which directly acetylates and stimulates the protein kinase ULK1, which is required for autophagy. Cells engineered to express TIP60(S86A) that cannot be phosphorylated by GSK3 could not undergo serum deprivation-induced autophagy. An acetylation-defective mutant of ULK1 failed to rescue autophagy in ULK1(-/-) mouse embryonic fibroblasts. Cells used signaling from GSK3 to TIP60 and ULK1 to regulate autophagy when deprived of serum but not glucose. These findings uncover an activating pathway that integrates protein phosphorylation and acetylation to connect growth factor deprivation to autophagy. 相似文献
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When not transporting cargo, kinesin-1 is autoinhibited by binding of a tail region to the motor domains, but the mechanism of inhibition is unclear. We report the crystal structure of a motor domain dimer in complex with its tail domain at 2.2 angstroms and compare it with a structure of the motor domain alone at 2.7 angstroms. These structures indicate that neither an induced conformational change nor steric blocking is the cause of inhibition. Instead, the tail cross-links the motor domains at a second position, in addition to the coiled coil. This "double lockdown," by cross-linking at two positions, prevents the movement of the motor domains that is needed to undock the neck linker and release adenosine diphosphate. This autoinhibition mechanism could extend to some other kinesins. 相似文献
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Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling 总被引:1,自引:0,他引:1
Yu Y Yoon SO Poulogiannis G Yang Q Ma XM Villén J Kubica N Hoffman GR Cantley LC Gygi SP Blenis J 《Science (New York, N.Y.)》2011,332(6035):1322-1326
The evolutionarily conserved serine-threonine kinase mammalian target of rapamycin (mTOR) plays a critical role in regulating many pathophysiological processes. Functional characterization of the mTOR signaling pathways, however, has been hampered by the paucity of known substrates. We used large-scale quantitative phosphoproteomics experiments to define the signaling networks downstream of mTORC1 and mTORC2. Characterization of one mTORC1 substrate, the growth factor receptor-bound protein 10 (Grb10), showed that mTORC1-mediated phosphorylation stabilized Grb10, leading to feedback inhibition of the phosphatidylinositol 3-kinase (PI3K) and extracellular signal-regulated, mitogen-activated protein kinase (ERK-MAPK) pathways. Grb10 expression is frequently down-regulated in various cancers, and loss of Grb10 and loss of the well-established tumor suppressor phosphatase PTEN appear to be mutually exclusive events, suggesting that Grb10 might be a tumor suppressor regulated by mTORC1. 相似文献
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胰岛素样生长因子-1的放射免疫测定方法的建立 总被引:13,自引:1,他引:13
胰岛素样生长因子-1(IGF-1)分别与两种载体蛋白——牛血清白蛋白(BSA)和卵清蛋白(OA)用戊二醛连接,经紫外分光光度仪扫描确定偶联成功。以IGF-1-BSA作为免疫原,皮内多点注射免疫青紫兰兔,制备IGF-1抗体,经ELISA法测定,血清效价为1∶2000,放免工作浓度为1∶15000。采用氯胺-T标记IGF-1,用酸醇抽提法处理样品,去除IGF-1结合蛋白。所建立的IGF-1放免标准曲线,其最小检测量为0.06ng/mL,批内误差为4.8%,批间误差为8.2%(n=10)。 相似文献
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Palmer LM Schulz JM Murphy SC Ledergerber D Murayama M Larkum ME 《Science (New York, N.Y.)》2012,335(6071):989-993
Interhemispheric inhibition is thought to mediate cortical rivalry between the two hemispheres through callosal input. The long-lasting form of this inhibition is believed to operate via γ-aminobutyric acid type B (GABA(B)) receptors, but the process is poorly understood at the cellular level. We found that the firing of layer 5 pyramidal neurons in rat somatosensory cortex due to contralateral sensory stimulation was inhibited for hundreds of milliseconds when paired with ipsilateral stimulation. The inhibition acted directly on apical dendrites via layer 1 interneurons but was silent in the absence of pyramidal cell firing, relying on metabotropic inhibition of active dendritic currents recruited during neuronal activity. The results not only reveal the microcircuitry underlying interhemispheric inhibition but also demonstrate the importance of active dendritic properties for cortical output. 相似文献
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Aricescu AR Siebold C Choudhuri K Chang VT Lu W Davis SJ van der Merwe PA Jones EY 《Science (New York, N.Y.)》2007,317(5842):1217-1220
Cell-cell contacts are fundamental to multicellular organisms and are subject to exquisite levels of control. Human RPTPmu is a type IIB receptor protein tyrosine phosphatase that both forms an adhesive contact itself and is involved in regulating adhesion by dephosphorylating components of cadherin-catenin complexes. Here we describe a 3.1 angstrom crystal structure of the RPTPmu ectodomain that forms a homophilic trans (antiparallel) dimer with an extended and rigid architecture, matching the dimensions of adherens junctions. Cell surface expression of deletion constructs induces intercellular spacings that correlate with the ectodomain length. These data suggest that the RPTPmu ectodomain acts as a distance gauge and plays a key regulatory function, locking the phosphatase to its appropriate functional location. 相似文献
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A mechanism of extreme growth and reliable signaling in sexually selected ornaments and weapons 总被引:1,自引:0,他引:1
Many male animals wield ornaments or weapons of exaggerated proportions. We propose that increased cellular sensitivity to signaling through the insulin/insulin-like growth factor (IGF) pathway may be responsible for the extreme growth of these structures. We document how rhinoceros beetle horns, a sexually selected weapon, are more sensitive to nutrition and more responsive to perturbation of the insulin/IGF pathway than other body structures. We then illustrate how enhanced sensitivity to insulin/IGF signaling in a growing ornament or weapon would cause heightened condition sensitivity and increased variability in expression among individuals--critical properties of reliable signals of male quality. The possibility that reliable signaling arises as a by-product of the growth mechanism may explain why trait exaggeration has evolved so many different times in the context of sexual selection. 相似文献
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恩诺沙星对雨生红球藻的生长抑制毒性测定 总被引:2,自引:0,他引:2
以雨生红球藻Haemafococcus pluvialis为研究对象,测定了恩诺沙星对雨生红球藻的生长抑制毒性.结果表明:在25℃条件下,24h时恩诺沙星对雨生红球藻的生长不产生抑制的最高质量浓度为50μg/mL,致使雨生红球藻完全死亡的最低质量浓度为180μg/mL.随时间的延长,雨生红球藻对恩诺沙星的耐受力增强.24、48h时恩诺沙星对雨生红球藻的EC50分别为119.67和152.29μg/mL.在天然水体中恩诺沙星不会对雨生红球藻的生长造成直接的抑制毒性. 相似文献
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Meiotic recombination in budding yeast requires two RecA-related proteins, Rad51 and Dmc1, both of which form filaments on DNA capable of directing homology search and catalyzing formation of homologous joint molecules (JMs) and strand exchange. With use of a separation-of-function mutant form of Rad51 that retains filament-forming but not JM-forming activity, we show that the JM activity of Rad51 is fully dispensable for meiotic recombination. The corresponding mutation in Dmc1 causes a profound recombination defect, demonstrating Dmc1's JM activity alone is responsible for meiotic recombination. We further provide biochemical evidence that Rad51 acts with Mei5-Sae3 as a Dmc1 accessory factor. Thus, Rad51 is a multifunctional protein that catalyzes recombination directly in mitosis and indirectly, via Dmc1, during meiosis. 相似文献
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Stimulation of phospholipase C-gamma 1 membrane association by epidermal growth factor 总被引:18,自引:0,他引:18
Epidermal growth factor (EGF) treatment of A-431 epidermoid carcinoma cells elicited a redistribution of phospholipase C-gamma 1 (PLC-gamma 1) from a predominantly cytosolic localization to membrane fractions. The temporal coincidence of this redistribution with EGF stimulation of inositol phosphate formation and EGF increased phosphorylation of PLC-gamma 1 suggests that the membrane association of PLC-gamma 1 is a significant event in second messenger transduction. 相似文献
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Fibroblast growth factor receptor is a portal of cellular entry for herpes simplex virus type 1 总被引:16,自引:0,他引:16
R J Kaner A Baird A Mansukhani C Basilico B D Summers R Z Florkiewicz D P Hajjar 《Science (New York, N.Y.)》1990,248(4961):1410-1413
Herpes simplex virus type 1 (HSV-1) is a ubiquitous pathogen responsible for considerable morbidity in the general population. The results presented herein establish the basic fibroblast growth factor (FGF) receptor as a means of entry of HSV-1 into vertebrate cells. Inhibitors of basic FGF binding to its receptor and competitive polypeptide antagonists of basic FGF prevented HSV-1 uptake. Chinese hamster ovary (CHO) cells that do not express FGF receptors are resistant to HSV-1 entry; however, HSV-1 uptake is dramatically increased in CHO cells transfected with a complementary DNA encoding a basic FGF receptor. The distribution of this integral membrane protein in vivo may explain the tissue and cell tropism of HSV-1. 相似文献
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文章阐述了在转录水平上精原干细胞在增殖与分化过程中的内在调节蛋白Plzf、Sohlh及其对精原干细胞的调节机制。介绍了胶质细胞源性神经营养因子、干细胞因子、Ets相关分子、骨形态发生蛋白、肝细胞生长因子、斯里兰卡肉桂碱受体等由支持细胞分泌的对精原细胞增殖与分化有重要作用的生长因子。 相似文献
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Women with mutations in the breast cancer susceptibility gene BRCA1 are predisposed to breast and ovarian cancers. Why the BRCA1 protein suppresses tumor development specifically in ovarian hormone-sensitive tissues remains unclear. We demonstrate that mammary glands of nulliparous Brca1/p53-deficient mice accumulate lateral branches and undergo extensive alveologenesis, a phenotype that occurs only during pregnancy in wild-type mice. Progesterone receptors, but not estrogen receptors, are overexpressed in the mutant mammary epithelial cells because of a defect in their degradation by the proteasome pathway. Treatment of Brca1/p53-deficient mice with the progesterone antagonist mifepristone (RU 486) prevented mammary tumorigenesis. These findings reveal a tissue-specific function for the BRCA1 protein and raise the possibility that antiprogesterone treatment may be useful for breast cancer prevention in individuals with BRCA1 mutations. 相似文献