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1.
Eukaryotic messenger RNAs contain a modified guanosine, termed a cap, at their 5' ends. Translation of mRNAs requires the binding of an initiation factor, eIF4E, to the cap structure. Here, we describe a family of proteins that through a shared sequence regulate cap-dependent translation. The biological importance of this translational regulation is immense, and affects such processes as cell growth, development, oncogenic transformation and perhaps even axon pathfinding and memory consolidation. 相似文献
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人翻译起始因子eIF4E是特异性识别并结合mRNA帽结构的蛋白质.该文通过克隆人源基因eIF4E,并利用原核细胞大肠杆菌BL21成功表达了具有帽结合功能的eIF4E蛋白,利用该蛋白亲和纯化分离得到了具有帽子结构的RNA.通过对比用oligo(dT)分离得到的非编码RNA,eIF4E法得到了更多种类的非编码RNA.本研究为非编码RNA的分离与发现提供了一个重要的工具. 相似文献
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探讨e IF4E在CXCL12诱导胃癌细胞形态学改变和迁移中的作用和机制.在胃癌细胞株(SGC7901,MGC803)上给予CXCL12处理,显微镜下观察细胞形态的改变;通过transwell实验检测CXCL12对胃癌细胞迁移能力的影响;在SGC7901上给予CXCL12处理,用Western blot检测e IF4E磷酸化和总蛋白水平的变化;用脂质体转染e IF4E的小干扰RNA,检测e IF4E对胃癌细胞形态学和迁移的影响;以及用qRT-PCR检测与肿瘤侵袭转移密切相关的因子MMP9的mRNA水平的表达.结果显示,给予CXCL12处理,胃癌细胞形态由上皮表型向长梭形的间叶样表型转变,细胞的迁移能力提高.在相同浓度的CXCL12处理情况下,转染e IF4E siRNA抑制e IF4E的表达,可抑制CXCL12诱导的细胞的形态学改变和迁移能力.另外,CXCL12引起与肿瘤转移密切相关因子MMP9的mRNA水平的表达升高,而用siRNA抑制e IF4E的表达,可下调MMP9的mRNA表达水平.结论:CXCL12激活了e IF4E,阻抑e IF4E的表达抑制CXCL12诱导的形态学改变和细胞迁移,其作用机制可能与上调MMP9的表达有关. 相似文献
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目的:探讨乳腺癌组织中CD163~+肿瘤相关巨噬细胞的浸润情况与eIF4E表达及其与临床病理特征的关系,并分析两者的相关性.方法:收集乳腺癌组织92例及癌旁正常乳腺组织74例,应用Maxvision法进行免疫组化染色检测eIF4E及CD163表达,并分析其与乳腺癌临床病理特征的关系.结果:乳腺癌组织中的CD163表达量高于癌旁正常组织(P0.001),乳腺癌组织中的eIF4E表达量高于癌旁正常乳腺组织(P0.001),CD163的表达与ki67表达相关(P0.05),CD163与eIF4E的表达呈正相关(r=0.273,P0.05).结论:乳腺癌中CD163和eIF4E的表达明显高于癌旁组织,CD163的过表达与ki67的表达相关,同时与eIF4E呈正相关,提示CD163与eIF4E的共同作用可能参与了乳腺癌的发生与发展. 相似文献
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Wnt signalling in stem cells and cancer 总被引:3,自引:0,他引:3
The canonical Wnt cascade has emerged as a critical regulator of stem cells. In many tissues, activation of Wnt signalling has also been associated with cancer. This has raised the possibility that the tightly regulated self-renewal mediated by Wnt signalling in stem and progenitor cells is subverted in cancer cells to allow malignant proliferation. Insights gained from understanding how the Wnt pathway is integrally involved in both stem cell and cancer cell maintenance and growth in the intestinal, epidermal and haematopoietic systems may serve as a paradigm for understanding the dual nature of self-renewal signals. 相似文献
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Kim BG Li C Qiao W Mamura M Kasprzak B Kasperczak B Anver M Wolfraim L Hong S Mushinski E Potter M Kim SJ Fu XY Deng C Letterio JJ 《Nature》2006,441(7096):1015-1019
SMAD4 (MAD homologue 4 (Drosophila)), also known as DPC4 (deleted in pancreatic cancer), is a tumour suppressor gene that encodes a central mediator of transforming growth factor-beta signalling. Germline mutations in SMAD4 are found in over 50% of patients with familial juvenile polyposis, an autosomal dominant disorder characterized by predisposition to hamartomatous polyps and gastrointestinal cancer. Dense inflammatory cell infiltrates underlay grossly normal appearing, non-polypoid colonic and gastric mucosa of patients with familial juvenile polyposis. This prominent stromal component suggests that loss of SMAD4-dependent signalling in cells within the epithelial microenvironment has an important role in the evolution of intestinal tumorigenesis in this syndrome. Here we show that selective loss of Smad4-dependent signalling in T cells leads to spontaneous epithelial cancers throughout the gastrointestinal tract in mice, whereas epithelial-specific deletion of the Smad4 gene does not. Tumours arising within the colon, rectum, duodenum, stomach and oral cavity are stroma-rich with dense plasma cell infiltrates. Smad4(-/-) T cells produce abundant T(H)2-type cytokines including interleukin (IL)-5, IL-6 and IL-13, known mediators of plasma cell and stromal expansion. The results support the concept that cancer, as an outcome, reflects the loss of the normal communication between the cellular constituents of a given organ, and indicate that Smad4-deficient T cells ultimately send the wrong message to their stromal and epithelial neighbours. 相似文献
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The Hedgehog and Wnt signalling pathways in cancer 总被引:53,自引:0,他引:53
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Ridgway J Zhang G Wu Y Stawicki S Liang WC Chanthery Y Kowalski J Watts RJ Callahan C Kasman I Singh M Chien M Tan C Hongo JA de Sauvage F Plowman G Yan M 《Nature》2006,444(7122):1083-1087
Haploinsufficiency of Dll4, a vascular-specific Notch ligand, has shown that it is essential for embryonic vascular development and arteriogenesis. Mechanistically, it is unclear how the Dll4-mediated Notch pathway contributes to complex vascular processes that demand meticulous coordination of multiple signalling pathways. Here we show that Dll4-mediated Notch signalling has a unique role in regulating endothelial cell proliferation and differentiation. Neutralizing Dll4 with a Dll4-selective antibody rendered endothelial cells hyperproliferative, and caused defective cell fate specification or differentiation both in vitro and in vivo. In addition, blocking Dll4 inhibited tumour growth in several tumour models. Remarkably, antibodies against Dll4 and antibodies against vascular endothelial growth factor (VEGF) had paradoxically distinct effects on tumour vasculature. Our data also indicate that Dll4-mediated Notch signalling is crucial during active vascularization, but less important for normal vessel maintenance. Furthermore, unlike blocking Notch signalling globally, neutralizing Dll4 had no discernable impact on intestinal goblet cell differentiation, supporting the idea that Dll4-mediated Notch signalling is largely restricted to the vascular compartment. Therefore, targeting Dll4 might represent a broadly efficacious and well-tolerated approach for the treatment of solid tumours. 相似文献
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Yauch RL Gould SE Scales SJ Tang T Tian H Ahn CP Marshall D Fu L Januario T Kallop D Nannini-Pepe M Kotkow K Marsters JC Rubin LL de Sauvage FJ 《Nature》2008,455(7211):406-410
Ligand-dependent activation of the hedgehog (Hh) signalling pathway has been associated with tumorigenesis in a number of human tissues. Here we show that, although previous reports have described a cell-autonomous role for Hh signalling in these tumours, Hh ligands fail to activate signalling in tumour epithelial cells. In contrast, our data support ligand-dependent activation of the Hh pathway in the stromal microenvironment. Specific inhibition of Hh signalling using small molecule inhibitors, a neutralizing anti-Hh antibody or genetic deletion of smoothened (Smo) in the mouse stroma results in growth inhibition in xenograft tumour models. Taken together, these studies demonstrate a paracrine requirement for Hh ligand signalling in the tumorigenesis of Hh-expressing cancers and have important implications for the development of Hh pathway antagonists in cancer. 相似文献
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Parsons DW Wang TL Samuels Y Bardelli A Cummins JM DeLong L Silliman N Ptak J Szabo S Willson JK Markowitz S Kinzler KW Vogelstein B Lengauer C Velculescu VE 《Nature》2005,436(7052):792
Protein kinases are enzymes that are important for controlling cellular growth and invasion, and their malfunction is implicated in the development of some tumours. We analysed human colorectal cancers for genetic mutations in 340 serine/threonine kinases and found mutations in eight genes, including in three members of the phosphatidylinositol-3-OH kinase (PI(3)K) pathway. The discovery of this mutational activation of a key cell-signalling pathway may provide new targets for therapeutic intervention. 相似文献
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Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer 总被引:41,自引:0,他引:41
Embryonic signalling pathways regulate progenitor cell fates in mammalian epithelial development and cancer. Prompted by the requirement for sonic hedgehog (Shh) signalling in lung development, we investigated a role for this pathway in regeneration and carcinogenesis of airway epithelium. Here we demonstrate extensive activation of the hedgehog (Hh) pathway within the airway epithelium during repair of acute airway injury. This mode of Hh signalling is characterized by the elaboration and reception of the Shh signal within the epithelial compartment, and immediately precedes neuroendocrine differentiation. We reveal a similar pattern of Hh signalling in airway development during normal differentiation of pulmonary neuroendocrine precursor cells, and in a subset of small-cell lung cancer (SCLC), a highly aggressive and frequently lethal human tumour with primitive neuroendocrine features. These tumours maintain their malignant phenotype in vitro and in vivo through ligand-dependent Hh pathway activation. We propose that some types of SCLC might recapitulate a critical, Hh-regulated event in airway epithelial differentiation. This requirement for Hh pathway activation identifies a common lethal malignancy that may respond to pharmacological blockade of the Hh signalling pathway. 相似文献
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The specification of both the germ line and abdomen in Drosophila depends on the localization of oskar messenger RNA to the posterior of the oocyte. This localization requires several trans-acting factors, including Barentsz and the Mago-Y14 heterodimer, which assemble with oskar mRNA into ribonucleoprotein particles (RNPs) and localize with it at the posterior pole. Although Barentsz localization in the germ line depends on Mago-Y14, no direct interaction between these proteins has been detected. Here, we demonstrate that the translation initiation factor eIF4AIII interacts with Barentsz and is a component of the oskar messenger RNP localization complex. Moreover, eIF4AIII interacts with Mago-Y14 and thus provides a molecular link between Barentsz and the heterodimer. The mammalian Mago (also known as Magoh)-Y14 heterodimer is a component of the exon junction complex. The exon junction complex is deposited on spliced mRNAs and functions in nonsense-mediated mRNA decay (NMD), a surveillance mechanism that degrades mRNAs with premature translation-termination codons. We show that both Barentsz and eIF4AIII are essential for NMD in human cells. Thus, we have identified eIF4AIII and Barentsz as components of a conserved protein complex that is essential for mRNA localization in flies and NMD in mammals. 相似文献
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Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4 总被引:25,自引:0,他引:25
Yamamoto M Sato S Hemmi H Sanjo H Uematsu S Kaisho T Hoshino K Takeuchi O Kobayashi M Fujita T Takeda K Akira S 《Nature》2002,420(6913):324-329
Signal transduction through Toll-like receptors (TLRs) originates from their intracellular Toll/interleukin-1 receptor (TIR) domain, which binds to MyD88, a common adaptor protein containing a TIR domain. Although cytokine production is completely abolished in MyD88-deficient mice, some responses to lipopolysaccharide (LPS), including the induction of interferon-inducible genes and the maturation of dendritic cells, are still observed. Another adaptor, TIRAP (also known as Mal), has been cloned as a molecule that specifically associates with TLR4 and thus may be responsible for the MyD88-independent response. Here we report that LPS-induced splenocyte proliferation and cytokine production are abolished in mice lacking TIRAP. As in MyD88-deficient mice, LPS activation of the nuclear factor NF-kappaB and mitogen-activated protein kinases is induced with delayed kinetics in TIRAP-deficient mice. Expression of interferon-inducible genes and the maturation of dendritic cells is observed in these mice; they also show defective response to TLR2 ligands, but not to stimuli that activate TLR3, TLR7 or TLR9. In contrast to previous suggestions, our results show that TIRAP is not specific to TLR4 signalling and does not participate in the MyD88-independent pathway. Instead, TIRAP has a crucial role in the MyD88-dependent signalling pathway shared by TLR2 and TLR4. 相似文献
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Oct4 is mainly expressed in embryonic stem cells(ESCs),germline stem cells,and embryonal carcinoma cells(ECCs)and plays an indispensable role in maintaining the pluripotency and self-renewal of these pluripotent stem cells.Akt serine/threonine kinase,a wellestablished anti-apoptosis and cell survival factor,has also been implicated as an important regulator of stemness.Emerging evidence indicated that Oct4 is reciprocally connected to Akt via a number of routes,and moreover,a direct interaction between Oct4 and Akt has recently been revealed.These components collectively form the Akt–Oct4 regulatory circuit.In this review,we summarize our current knowledge about the Akt–Oct4 regulatory circuit in ESCs and discuss its alterations in ECCs that may underlie the tumorigenesis of pluripotent stem cells. 相似文献
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Hsieh AC Liu Y Edlind MP Ingolia NT Janes MR Sher A Shi EY Stumpf CR Christensen C Bonham MJ Wang S Ren P Martin M Jessen K Feldman ME Weissman JS Shokat KM Rommel C Ruggero D 《Nature》2012,485(7396):55-61
The mammalian target of rapamycin (mTOR) kinase is a master regulator of protein synthesis that couples nutrient sensing to cell growth and cancer. However, the downstream translationally regulated nodes of gene expression that may direct cancer development are poorly characterized. Using ribosome profiling, we uncover specialized translation of the prostate cancer genome by oncogenic mTOR signalling, revealing a remarkably specific repertoire of genes involved in cell proliferation, metabolism and invasion. We extend these findings by functionally characterizing a class of translationally controlled pro-invasion messenger RNAs that we show direct prostate cancer invasion and metastasis downstream of oncogenic mTOR signalling. Furthermore, we develop a clinically relevant ATP site inhibitor of mTOR, INK128, which reprograms this gene expression signature with therapeutic benefit for prostate cancer metastasis, for which there is presently no cure. Together, these findings extend our understanding of how the 'cancerous' translation machinery steers specific cancer cell behaviours, including metastasis, and may be therapeutically targeted. 相似文献
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Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4 总被引:33,自引:0,他引:33
Suzuki N Suzuki S Duncan GS Millar DG Wada T Mirtsos C Takada H Wakeham A Itie A Li S Penninger JM Wesche H Ohashi PS Mak TW Yeh WC 《Nature》2002,416(6882):750-756
Toll-like receptors (TLRs), which recognize pathogen-associated molecular patterns, and members of the pro-inflammatory interleukin-1 receptor (IL-1R) family, share homologies in their cytoplasmic domains called Toll/IL-1R/plant R gene homology (TIR) domains. Intracellular signalling mechanisms mediated by TIRs are similar, with MyD88 (refs 5-8) and TRAF6 (refs 9, 10) having critical roles. Signal transduction between MyD88 and TRAF6 is known to involve the serine-threonine kinase IL-1 receptor-associated kinase 1 (IRAK-1) and two homologous proteins, IRAK-2 (ref. 12) and IRAK-M. However, the physiological functions of the IRAK molecules remain unclear, and gene-targeting studies have shown that IRAK-1 is only partially required for IL-1R and TLR signalling. Here we show by gene-targeting that IRAK-4, an IRAK molecule closely related to the Drosophila Pelle protein, is indispensable for the responses of animals and cultured cells to IL-1 and ligands that stimulate various TLRs. IRAK-4-deficient animals are completely resistant to a lethal dose of lipopolysaccharide (LPS). In addition, animals lacking IRAK-4 are severely impaired in their responses to viral and bacterial challenges. Our results indicate that IRAK-4 has an essential role in innate immunity. 相似文献
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鉴于野外生存训练的教育价值和社会价值,对其引入高校体育教育的必要性进行分析,并针对我国高校开展野外生存训练的实际情况,讨论具体的实施策略及保障措施。文章结论对野外生存训练的发展和高校教育改革具有一定的参考价值。 相似文献