《BMC免疫学》：醉酒会使免疫功能下降 一项最新研究显示，酩酊大醉带来的不仅是酒醒后的头痛，还有免疫系统功能下降，酒精对一些免疫功能的抑制会超过24小时。 美国科研人员在新一期英国《BMC免疫学》（ BMC Immunology ）杂志上报告说，他们检测了实验鼠在短时间内饮下大量酒精后其免疫系统所受影响。结果发现，酒精会抑制名为TLR4的蛋白质的作用，而这种蛋白质是许多有免疫作用的细胞因子的信号员，这些细胞因子被激活后会引发炎症等免疫反应，以帮助机体对抗细菌和病毒等。 实验显示，这些信号员在人醉酒后不能好好站岗，即便在醉酒24小时后，一些细胞因子仍然不能被激活。 研究人员因此提醒，大醉一场至少会带来24小时的免疫功能低下期，经常醉酒的人要警惕感染各种疾病的风险。 http://www.sciencenet.cn/htmlnews/2009/9/223536.shtm 更多阅读 物理学家组织网相关报道（英文） 《BMC免疫学》发表论文摘要（英文） http://www.biomedcentral.com/1471-2172/10/49/abstract Ethanol inhibits LPS-induced signaling and modulates cytokine production in peritoneal macrophages in vivo in a model for binge drinking Stephen B Pruett and Ruping Fan BMC Immunology 2009, 10:49 doi:10.1186/1471-2172-10-49 Published: 18September2009 Abstract (provisional) Background Previous reports indicate that ethanol, in a binge drinking model in mice, inhibits the production of pro-inflammatory cytokines in vivo. However, the inhibition of signaling through TLR4 has not been investigated in this experimental model in vivo. Considering evidence that signaling can be very different in vitro and in vivo, the present study was conducted to determine if effects of ethanol on TLR4 signaling reported for cells in culture or cells removed from ethanol treated mice and stimulated in culture also occur when ethanol treatment and TLR4 activation occur in vivo. Results Phosphorylated p38, ERK, and c-Jun (nuclear) were quantified with kits or by western blot using samples taken 15, 30, and 60 min after stimulation of peritoneal macrophages with lipopolysaccharide in vivo. Effects of ethanol were assessed by administering ethanol by gavage at 6 g/kg 30 min before administration of lipopolysaccharide (LPS). Cytokine concentrations in the samples of peritoneal lavage fluid and in serum were determined at 1, 2, and 6 hr after lipopolysaccharide administration. All of these data were used to measure the area under the concentration vs time curve, which provided an indication of the overall effects of ethanol in this system. Ethanol suppressed production of most pro-inflammatory cytokines to a similar degree as it inhibited key TLR4 signaling events. However, NF-kappaB (p65) translocation to the nucleus was not inhibited by ethanol. To determine if NF-kappaB composed of other subunits was inhibited, transgenic mice with a luciferase reporter were used. This revealed a reproducible inhibition of NF-kappaB activity, which is consistent with the observed inhibition of cytokines whose expression is known to be NF-kappaB dependent. Conclusions Overall, the effects of ethanol on signalling in vivo were similar to those reported for in vivo exposure to ethanol and/or lipopolysaccharide. However, inhibition of the activation of NF-kappaB was not detected as translocation of p65 to the nucleus but was detected using transgenic reporter mice. The observation that ethanol given 24 hr before dosing with LPS modulated production of some cytokines indicates a persistent effect which does not require continued presence of ethanol. 信息分析平台： http://www.gopubmed.org/web/gopubmed/WEB1mOWEB10O00d000j10020001000d000j100300.y 检索策略：TLR4 and drinking 相关文献计量分析结果： Top Years Publications 2008 6 2007 3 2004 3 2009 2 2006 1 2005 1 2001 1 Top Countries Publications USA 7 Japan 3 Israel 3 Canada 1 Taiwan 1 South Korea 1 France 1 Top Cities Publications Shreveport 2 Haifa 2 Osaka 1 Kyoto 1 Toronto 1 Cleveland 1 Taipei 1 Anyang, South Korea 1 Lille 1 Worcester 1 Boston 1 Sapporo 1 Urbana 1 Bethesda 1 Top Journals Publications Clin Exp Immunol 3 Am J Physiol Gastrointest Liver Physiol 1 J Gastroenterol Hepatol 1 J Immunotoxicol 1 Am J Reprod Immunol 1 Methods Mol Biol 1 Shock 1 Digest Dis Sci 1 Med Mycol 1 Pancreatology 1 Infect Immun 1 Alcohol 1 Physiol Behav 1 Gastroenterology 1 Alcohol Clin Exp Res 1 1 2 3 4 5 Top Authors Publications Pruett S 2 Sukhotnik I 2 Mogilner J 2 Lurie M 2 Takeda K 2 Akira S 2 Arakawa T 1 Watanabe T 1 Nishio H 1 Tanigawa T 1 Yamagami H 1 Okazaki H 1 Watanabe K 1 Tominaga K 1 Fujiwara Y 1 Oshitani N 1 Asahara T 1 Nomoto K 1 Higuchi K 1 Takeuchi K 1 1 2 3 4 5 1 2 3 ... 22 Top Terms Publications tlr4 14 Animals 14 Mice 12 Toll-Like Receptor 4 11 Toll-Like Receptors 11 Tumor Necrosis Factor-alpha 8 Lipopolysaccharides 8 tlr 7 Cytokines 7 Macrophages 7 gut development 6 RNA, Messenger 6 Proteins 6 Intestines 6 Wounds and Injuries 5 Necrosis 5 Evaluation Studies as Topic 5 signal transduction 5 programmed cell death 5 Monocytes 5 1 2 3 ... 22 相关研究报道： Title: Probiotic Lactobacillus casei strain Shirota prevents indomethacin-induced small intestinal injury: involvement of lactic acid. PMID: 19589943 Related Articles Authors: Watanabe, T , et.al. Journal: Am J Physiol Gastrointest Liver Physiol , Vol. 297 (3): G506-13 , 2009 Snippet: One-week treatment with viable LcS prevented indomethacin-induced intestinal injury with increase in the concentration of lactic acid in small intestinal content and inhibited increases in myeloperoxidase activity and expression of mRNA for tumor necrosis factor-alpha ( TNF-alpha ) while affecting neither TLR4 expression nor the number of gram-negative bacteria in intestinal content, whereas neither heat-killed LcS nor a single dose of viable LcS inhibited intestinal injury. Affiliation: Dept. of Gastroenterology, Osaka City Univ. Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan . watanabet@med.osaka-cu.ac.jp Title: Isoflavones regulate innate immunity and inhibit experimental colitis. PMID: 19220665 Related Articles Authors: Morimoto, M , et.al. Journal: J Gastroenterol Hepatol , Vol. 24 (6): 1123-9 , 2009 Snippet: METHODS: We administered daidzein-rich isoflavone aglycones (DRIA) to mice for 1 week and then treated them with 2% dextran sodium sulfate (DSS) in drinking water for 4 days to induce colitis. Affiliation: Department of Clinical Bio-regulatory Science, Kyoto University Graduate School of Medicine, Kyoto , Japan . Title: Different Effects of Acute and Chronic Ethanol on LPS-Induced Cytokine Production and TLR4 Receptor Behavior in Mouse Peritoneal Macrophages. PMID: 18958703 Related Articles Authors: Dai, Q , et.al. Journal: J Immunotoxicol , Vol. 3 (4): 217-25 , 2006 Snippet: Both binge and chronic heavy drinking can adversely affect the immune system, but the effects seem to be at least partly dependent on the manner of ethanol (EtOH) consumption. Affiliation: Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport , LA , USA . Title: LPS -induced murine abortions require C5 but not C3 , and are prevented by upregulating expression of the CD200 tolerance signaling molecule. PMID: 18705840 Related Articles Authors: Yu, G , et.al. Journal: Am J Reprod Immunol , Vol. 60 (2): 135-40 , 2008 Snippet: PROBLEM: Lipopolysaccharide (LPS) acts via tlr4 to promote Th1 cytokine secretion and abortions. Affiliation: Toronto General Research Institute CIHR Group on Cellular and Molecular Mechanisms of Organ Injury, Institute of Medical Sciences, University of Toronto, Toronto , Ontario , Canada . Title: Isolation of Kupffer cells from rats fed chronic ethanol. PMID: 18369921 Related Articles Authors: McMullen, M R , et.al. Journal: Methods Mol Biol , Vol. 447 , 2008 Snippet: Activation of Kupffer cells leads to an increased production of proinflammatory cytokines, such as tumor necrosis factor-alpha and also reactive oxygen species, a process mediated in part by changes in lipopolysaccharide-induced TLR4 -dependent signal transduction. Affiliation: Department Pathobiology, Cleveland Clinic, Cleveland , OH , USA . Title: TLR ligand decreases mesenteric ischemia and reperfusion injury-induced gut damage through TNF-alpha signaling. PMID: 18317407 Related Articles Authors: Chen, L , et.al. Journal: Shock , Vol. 30 (5): 563-70 , 2008 Snippet: We hypothesize that LPS, a ligand for TLR4 , decreases mesenteric I/R injury-induced gut damage through tumor necrosis factor alpha ( TNF-alpha ) signaling. Affiliation: Institute of Emergency and Critical Care Medicine, National Yang-Ming University, Taipei . chenlw2001@yahoo.com.tw Title: Treatment with glutamine is associated with down-regulation of Toll-like receptor-4 and myeloid differentiation factor 88 expression and decrease in intestinal mucosal injury caused by lipopolysaccharide endotoxaemia in a rat. PMID: 18070149 Related Articles Authors: Kessel, A , et.al. Journal: Clin Exp Immunol , Vol. 151 (2): 341-7 , 2008 Snippet: For this purpose, male Sprague-Dawley rats were assigned randomly to one of three experimental groups of 10 rats each: (i) control rats underwent intraperitoneal (i.p.) injection of sterile saline once a day; (ii) rats were treated with LPS given i.p. once a day at a dose of 10 mg/kg for 48 h (two doses); and (iii) rats were pretreated with oral Gln given in drinking water (2%) 48 h before and following injection of LPS. Affiliation: Allergy and Clinical Immunology, Bnai Zion Medical Center, The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa , Israel . aharon.kessel@b-zion.org.il Title: Lactobacillus casei prevents the development of dextran sulphate sodium-induced colitis in Toll-like receptor 4 mutant mice. PMID: 18005362 Related Articles Authors: Chung, Y W , et.al. Journal: Clin Exp Immunol , Vol. 151 (1): 182-9 , 2008 Snippet: TLR -4(lps-/lps-) and wild-type (WT) mice were given 2.5% dextran sulphate sodium (DSS) in drinking water to induce colitis with or without Lactobacillus casei pretreatment. Affiliation: Department of Gastroenterology, Hallym University Sacred Heart Hospital, Anyang , Korea . Title: Oral insulin up-regulates Toll-like receptor 4 expression and enhances intestinal recovery following lipopolysaccharide-induced gut injury in a rat. PMID: 17934814 Related Articles Authors: Sukhotnik, I , et.al. Journal: Dig Dis Sci , Vol. 53 (5): 1231-9 , 2008 Snippet: Male Sprague-Dawley rats were divided into three experimental groups: Sham rats, LPS-rats that were treated with lipopolysaccharide (LPS), and LPS-INS rats that were treated with OI given in drinking water 72 h before and following injection of LPS. Affiliation: Department of Pediatric Surgery B, Bnai Zion Medical Center, Haifa , Israel . igor-dr@internet-zahav.net Title: Saccharomyces boulardii decreases inflammation and intestinal colonization by Candida albicans in a mouse model of chemically-induced colitis. PMID: 17885943 Related Articles Authors: Jawhara, S , et.al. Journal: Med Mycol , Vol. 45 (8): 691-700 , 2007 Snippet: A 1.5% solution of DSS was administered in drinking water 1 h after C. albicans oral challenge, while 10(7) cells of S. boulardii was inoculated daily by oral gavage for 1 week. Affiliation: Inserm U 799, Physiopathologie des Candidoses, Facult de Mdecine, CHRU Lille , France . Effect of ethanol on inflammatory responses. Implications for pancreatitis. PMID: 17592223 Related Articles Authors: Szab, G , et.al. Journal: Pancreatology , Vol. 7 (2-3): 115-23 , 2007 Snippet: In contrast, acute alcohol treatment augmented NF -kappaB activation and TNFalpha production and inhibited IL-10 levels in the presence of complex stimulation with combined TLR2 and TLR4 ligands. Affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester , Massachusetts , USA . gyongyi.szabo@umassmed.edu Title: Resistance to Pseudomonas aeruginosa chronic lung infection requires cystic fibrosis transmembrane conductance regulator-modulated interleukin-1 ( IL-1 ) release and signaling through the IL-1 receptor . PMID: 17283089 Related Articles Authors: Reiniger, N , et.al. Journal: Infect Immun , Vol. 75 (4): 1598-608 , 2007 Snippet: We found neither Toll-like receptor 2 ( TLR2 ) nor TLR4 nor TLR5 were required for this response. Affiliation: Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, 181 Longwood Avenue, Boston , MA 02115, USA . Title: Macrophage migration inhibitory factor contributes to the development of acute dextran sulphate sodium-induced colitis in Toll-like receptor 4 knockout mice. PMID: 16045730 Related Articles Authors: Ohkawara, T , et.al. Journal: Clin Exp Immunol , Vol. 141 (3): 412-21 , 2005 Snippet: TLR4 (-/-) mice were given 2% dextran sulphate sodium (DSS) in drinking water to induce colitis, which was clinically and histologically as severe as that seen in wild-type (WT) mice. Affiliation: Department of Gastroenterology and Hematology, Hokkaido University Graduate School of Medicine, Sapporo , Japan . tokawara@med.hokudai.ac.jp Title: Ethanol suppresses cytokine responses induced through Toll -like receptors as well as innate resistance to Escherichia coli in a mouse model for binge drinking . PMID: 15528012 Related Articles Authors: Pruett, S B , et.al. Journal: Alcohol , Vol. 33 (2): 147-55 , 2004 Snippet: It has been reported that acute administration of ethanol suppresses responses mediated through TLR3 and TLR4 . Affiliation: Department of Cellular Biology and Anatomy, LSU Health Sciences Center, 1501 Kings Highway, Shreveport , LA 71130, USA . spruet@LSUHSC.edu Title: Dehydroepiandrosterone-sulfate did not mitigate sickness behavior in mice. PMID: 15327921 Related Articles Authors: Chen, J , et.al. Journal: Physiol Behav , Vol. 82 (4): 713-9 , 2004 Snippet: Mice were provided drinking water with 0% or 0.01% DHEA-S for 2 weeks and then injected intraperitoneally with saline or LPS (1 microg). Affiliation: Division of Nutritional Sciences, Department of Animal Sciences, University of Illinois, 1207 West Gregory Drive, Urbana , IL 61801, USA . Title: Toll-like receptor 9 signaling mediates the anti-inflammatory effects of probiotics in murine experimental colitis. PMID: 14762789 Related Articles Authors: Rachmilewitz, D , et.al. Journal: Gastroenterology , Vol. 126 (2): 520-8 , 2004 Snippet: Viable or gamma-irradiated probiotics were administered i.g. to wild-type mice and mice deficient in different TLR or in the adaptor protein MyD88, 10 days prior to administration of dextran sodium sulfate (DSS) to their drinking water and for 7 days thereafter. Affiliation: Division of Medicine, Shaare Zedak Medical Center, Jerusalem, Israel . Title: Pro- and anti-inflammatory gene expression in the murine small intestine and liver after chronic exposure to alcohol . PMID: 11329499 Related Articles Authors: Fleming, S D , et.al. Journal: Alcohol Clin Exp Res , Vol. 25 (4): 579-89 , 2001 Snippet: In the current study, we hypothesized that alcohol would alter cytokine expression within the small intestine of mice exposed to ethanol and that LPS would alter levels of cytokine expression even more dramatically. Affiliation: Department of Microbiology, Uniformed Services University of the Health Sciences, Bethesda , MD 20814, USA .
http://www.sciencenet.cn/htmlpaper/20099181122275007324.shtm 发现RAF蛋白激酶激活机制 蒙特利尔大学的研究人员Marc Therrien等人发现了RAF蛋白激酶的激活机制，而超过25%的癌症都与RAF蛋白激酶突变有关，了解该机制对开发全新的抗癌药物，降低化疗引起的毒副作用具有重要的意义。研究结果在线发表于9月2日的《自然》（ Nature ）杂志。 RAF激酶家族能调节细胞生长、分化以及生存等一系列生命过程。Therrien及其同事Sicheri首次证实，两个RAF蛋白发生二聚化对激活该蛋白至关重要。如果抑制RAF二聚化则会阻断激活过程，从而终止癌细胞的生长。 该研究不仅发现了RAF的激活机制，还揭示了控制其他蛋白激酶的潜在机制许多激酶都与癌症或其他疾病(如糖尿病，高血压，神经退行性疾病等)的发病有关。（来源：生物谷） 更多阅读 《自然》发表论文摘要（英文） http://www.nature.com/nature/journal/vaop/ncurrent/abs/nature08314.html Nature advance online publication 2 September 2009 | :10.1038/nature08314 :10.1038/nature08314 ; Received 10 April 2009; Accepted 24 July 2009; Published online 2 September 2009 A dimerization-dependent mechanism drives RAF catalytic activation Thanashan Rajakulendran 1 , 2 , 5 , Malha Sahmi 3 , 5 , Martin Lefranois 3 , Frank Sicheri 1 , 2 Marc Therrien 3 , 4 Centre for Systems Biology, Samuel Lunenfeld Research Institute, Toronto, Ontario M5G 1X5, Canada Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada Institute for Research in Immunology and Cancer, Laboratory of Intracellular Signaling, Dpartement de pathologie et de biologie cellulaire, Universit de Montral, Montral, Qubec H3C 3J7, Canada These authors contributed equally to this work. Correspondence to: Frank Sicheri 1 , 2 Marc Therrien 3 , 4 Correspondence and requests for materials should be addressed to F.S. (Email: sicheri@lunenfeld.ca ) or M.T. (Email: marc.therrien@umontreal.ca ). The ERK (extracellular signal-regulated kinase) pathway is an evolutionarily conserved signal transduction module that controls cellular growth, differentiation and survival 1 . Activation of receptor tyrosine kinases (RTKs) by the binding of growth factors initiates GTP loading of RAS, which triggers the initial steps in the activation of the ERK pathway by modulating RAF family kinase function. Once activated, RAF participates in a sequential cascade of phosphorylation events that activate MEK, and in turn ERK. Unbridled signalling through the ERK pathway caused by activating mutations in RTKs, RAS or RAF has been linked to several human cancers 2 . Of note, one member of the RAF family, BRAF, is the most frequently mutated oncogene in the kinase superfamily 3 . Not surprisingly, there has been a colossal effort to understand the underlying regulation of this family of kinases. In particular, the process by which the RAF kinase domain becomes activated towards its substrate MEK remains of topical interest. Here, using Drosophila Schneider S2 cells, we demonstrate that RAF catalytic function is regulated in response to a specific mode of dimerization of its kinase domain, which we term the side-to-side dimer. Moreover, we find that the RAF-related pseudo-kinase KSR (kinase suppressor of Ras) also participates in forming side-to-side heterodimers with RAF and can thereby trigger RAF activation. This mechanism provides an elegant explanation for the longstanding conundrum about RAF catalytic activation, and also provides an explanation for the capacity of KSR, despite lacking catalytic function, to directly mediate RAF activation. We also show that RAF side-to-side dimer formation is essential for aberrant signalling by oncogenic BRAF mutants, and identify an oncogenic mutation that acts specifically by promoting side-to-side dimerization. Together, our data identify the side-to-side dimer interface of RAF as a potential therapeutic target for intervention in BRAF-dependent tumorigenesis. 信息分析平台： http://www.gopubmed.org/web/gopubmed/1?WEB0150pg22ke0ehaI46I1I00d000j10040001rl 检索策略：RAF catalytic and oncogenic mutation 相关文献计量分析结果： Top Years Publications 1997 5 2004 4 2009 2 2008 1 2007 1 2006 1 2005 1 2003 1 2000 1 Top Countries Publications USA 9 Canada 2 United Kingdom 2 Germany 1 Japan 1 Spain 1 Australia 1 Top Cities Publications New York 2 Palo Alto 2 Toronto 1 San Antonio 1 Erlangen 1 Sapporo 1 Montreal 1 Houston 1 Glasgow 1 Salamanca 1 London 1 Chicago 1 Indianapolis 1 Top Journals Publications Oncogene 3 J Biol Chem 2 Cell 2 Mol Cell Biol 2 Nature 1 Future Oncol 1 Langenbecks Arch Surg 1 Carcinogenesis 1 Gene Dev 1 Cancer Cell 1 Cancer Res 1 Gene 1 1 2 3 ... 22 Top Terms Publications Oncogenes 16 Mutation 15 Phosphotransferases 14 Animals 14 ras 13 Catalytic Domain 13 Proteins 12 Protein Kinases 11 Proto-Oncogene Proteins c-raf 11 mek 10 Humans 10 signal transduction 9 catalytic activity 9 Phosphorylation 9 raf 9 protein serine/threonine kinase activity 9 phosphorylation 8 erk 8 Mitogen-Activated Protein Kinases 8 Cell Transformation, Neoplastic 8 1 2 3 ... 22 1 2 3 4 5 Top Authors Publications McMahon M 2 Cherwinski H 2 Mita M 1 Mahalingam D 1 Sankhala K 1 Mita A 1 Giles F 1 Su G 1 Schnleben F 1 Qiu W 1 Remotti H 1 Hohenberger W 1 Shinomura Y 1 Nosho K 1 Yamamoto H 1 Takahashi T 1 Mikami M 1 Taniguchi H 1 Miyamoto N 1 Adachi Y 1 1 2 3 4 5 相关研究报道： A dimerization-dependent mechanism drives RAF catalytic activation. PMID: 19727074 Related Articles Authors: Rajakulendran, T , et.al. Journal: Nature , 2009 Snippet: We also show that RAF side-to-side dimer formation is essential for aberrant signalling by oncogenic BRAF mutants, and identify an oncogenic mutation that acts specifically by promoting side-to-side dimerization. Affiliation: Centre for Systems Biology, Samuel Lunenfeld Research Institute, Toronto , Ontario M5G 1X5, Canada Department of Molecular Genetics, University of Toronto, Toronto , Ontario M5S 1A8, Canada These authors contributed equally to this work. Title: Targeting the mTOR pathway using deforolimus in cancer therapy. PMID: 19374536 Related Articles Authors: Mahalingam, D , et.al. Journal: Future Oncol , Vol. 5 (3): 291-303 , 2009 Snippet: The mammalian target of rapamycin (mTOR) is an intracellular protein with a key role in cellular protein synthesis and energy balance that influences many aspects of cell growth and proliferation, including differentiation, cell-cycle progression, angiogenesis, protein degradation and apoptosis. mTOR can be activated by numerous oncogenic signals, such as growth factor activation through the EGF , IGF and VEGF receptors, mutation and silencing of the PTEN tumor suppressor gene, activating mutations in the PI3K catalytic subunit, Akt amplification and the Ras - Raf - MEK pathway. Affiliation: Institute for Drug Development, Cancer Research and Therapy Center, University of Texas Health Science Centre San Antonio , TX , USA . Mahalingam@uthscsa.edu Title: PIK3CA , KRAS , and BRAF mutations in intraductal papillary mucinous neoplasm/carcinoma (IPMN/C) of the pancreas. PMID: 18343945 Related Articles Authors: Schnleben, F , et.al. Journal: Langenbecks Arch Surg , Vol. 393 (3): 289-96 , 2008 Snippet: BACKGROUND AND AIMS: Recent studies have reported high frequencies of somatic mutations in the phosphoinositide-3-kinase catalytic -alpha ( PIK3CA ) gene in various human tumors. Affiliation: Department of General Surgery, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen , Germany . frank.schoenleben@gmx.de Title: Genetic and epigenetic profiling in early colorectal tumors and prediction of invasive potential in pT1 (early invasive) colorectal cancers. PMID: 17183069 Related Articles Authors: Nosho, K , et.al. Journal: Carcinogenesis , Vol. 28 (6): 1364-70 , 2007 Snippet: In the current study, we compared the frequencies of genetic and epigenetic alterations of the RAS - RAF and Wnt signaling pathways in flat-type and protruded-type tumors. Affiliation: First Department of Internal Medicine, Sapporo Medical University, Sapporo , Japan . nosho@sapmed.ac.jp Title: A KSR / CNK complex mediated by HYP , a novel SAM domain-containing protein, regulates RAS -dependent RAF activation in Drosophila. PMID: 16600912 Related Articles Authors: Douziech, M , et.al. Journal: Genes Dev , Vol. 20 (7): 807-19 , 2006 Snippet: By analogy to catalytically impaired, but conformationally active B- RAF oncogenic mutants, we discuss the possibility that KSR represents a natural allosteric inducer of RAF catalytic function. Affiliation: Institute for Research in Immunology and Cancer, Laboratory of Intracellular Signaling, Montral , Quebec , Canada . Title: B- Raf and Raf -1 are regulated by distinct autoregulatory mechanisms. PMID: 15710605 Related Articles Authors: Tran, N H , et.al. Journal: J Biol Chem , Vol. 280 (16): 16244-53 , 2005 Snippet: Ser(445) phosphorylation is important to the B- Raf activation mechanism, however, because mutation of this site to alanine increased the affinity of the regulatory domain for the catalytic domain and increased autoinhibition. Affiliation: Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston , Texas 77030, USA . Title: Oncogenic B- Raf mutations: crystal clear at last. PMID: 15093535 Related Articles Authors: Dhillon, A S , et.al. Journal: Cancer Cell , Vol. 5 (4): 303-4 , 2004 Snippet: The Raf / MEK / ERK pathway is a conserved signaling module controlling cell growth, proliferation, apoptosis, and differentiation. Affiliation: The Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, United Kingdom . Title: C3G -mediated suppression of oncogene-induced focus formation in fibroblasts involves inhibition of ERK activation, cyclin A expression and alterations of anchorage-independent growth. PMID: 15077165 Related Articles Authors: Guerrero, C A , et.al. Journal: Oncogene , Vol. 23 (28): 4885-93 , 2004 Snippet: Using full-length C3G and C3GDeltaCat mutant, lacking catalytic domain, we showed here that overexpression of cotransfected C3G or C3GDeltaCat inhibited oncogenic Hraslys12-mediated phosphorylation of ERK , without altering Ras and Raf -1 kinase activation. Affiliation: Centro de Investigacin del Cncer, IBMCC, Universidad de Salamanca-CSIC, 37007- Salamanca , Spain . Title: Mechanism of activation of the RAF - ERK signaling pathway by oncogenic mutations of B- RAF . PMID: 15035987 Related Articles Authors: Wan, P T , et.al. Journal: Cell , Vol. 116 (6): 855-67 , 2004 Snippet: The structures of wild type and oncogenic V599EB- RAF kinase domains in complex with the RAF inhibitor BAY43-9006 show that the activation segment is held in an inactive conformation by association with the P loop. Affiliation: Section of Structural Biology, The Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, London SW3 6JB, UK . Title: Oncogenic mutations in B- Raf : some losses yield gains. PMID: 15035978 Related Articles Authors: Hubbard, S R Journal: Cell , Vol. 116 (6): 764-6 , 2004 Snippet: A study by Wan et al. in this issue of Cell demonstrates that the majority of oncogenic mutations in the B- Raf protein kinase result in increased catalytic activity, through disruption of the autoinhibited state of the kinase domain. Affiliation: Skirball Institute of Biomolecular Medicine and Department of Pharmacology, New York University School of Medicine, New York , NY 10016, USA . Title: Identification of residues and domains of Raf important for function in vivo and in vitro. PMID: 12954633 Related Articles Authors: Harding, A , et.al. Journal: J Biol Chem , Vol. 278 (46): 45519-27 , 2003 Snippet: The strongest phenotype in the genetic screens was displayed by a S508N mutation that again did not correlate with a significant loss of kinase activity or membrane recruitment by oncogenic Ras in biochemical assays. Affiliation: Institute for Molecular Bioscience and Department of Molecular and Cellular Pathology, University of Queensland , Brisbane 4072, Australia . Title: Transfection of constitutively active mitogen-activated protein/ extracellular signal-regulated kinase kinase confers tumorigenic and metastatic potentials to NIH3T3 cells. PMID: 10749122 Related Articles Authors: Welch, D R , et.al. Journal: Cancer Res , Vol. 60 (6): 1552-6 , 2000 Snippet: Components of the MAP kinase pathways also cause oncogenic transformation in their constitutively active forms. Affiliation: Jake Gittlen Cancer Research Institute, The Pennsylvania State University College of Medicine, Hershey 17033-2390, USA . Title: Identification and characterization of R-ras3 : a novel member of the RAS gene family with a non-ubiquitous pattern of tissue distribution. PMID: 9400994 Related Articles Authors: Kimmelman, A C , et.al. Journal: Oncogene , Vol. 15 (22): 2675-85 , 1997 Snippet: An activating mutation corresponding to the leucine 61 oncogenic lesion of the ras oncogenes when introduced into R-ras3 , activates its transforming potential. Affiliation: The Derald H. Ruttenberg Cancer Center, Mount Sinai School of Medicine, New York , New York 10029, USA . Title: pXen, a utility vector for the expression of GST -fusion proteins in Xenopus laevis oocytes and embryos. PMID: 9322737 Related Articles Authors: Macnicol, M C , et.al. Journal: Gene , Vol. 196 (1-2): 25-9 , 1997 Snippet: The utility of pXen is demonstrated by cloning the catalytic domain of the serine/threonine kinase proto-oncogene Raf -1 into this vector and injecting the corresponding in vitro transcribed RNA into oocytes. Affiliation: Department of Medicine MC6088, University of Chicago , IL 60637, USA . Title: Mutations of critical amino acids affect the biological and biochemical properties of oncogenic A- Raf and Raf -1 . PMID: 9285556 Related Articles Authors: Bosch, E , et.al. Journal: Oncogene , Vol. 15 (9): 1021-33 , 1997 Snippet: In Raf -1 the phosphorylation or mutation to aspartic acid of two key tyrosine residues upstream of the ATP binding site has been demonstrated to significantly potentiate catalytic activity. Affiliation: Department of Cell Signaling, DNAX Research Institute, Palo Alto , California 94304-1104, USA . Title: Phosphorylation of Raf -1 serine 338-serine 339 is an essential regulatory event for Ras -dependent activation and biological signaling. PMID: 9234708 Related Articles Authors: Daz, B , et.al. Journal: Mol Cell Biol , Vol. 17 (8): 4509-16 , 1997 Snippet: Phosphorylation of either tyrosine 340 or 341 in the catalytic domain of Raf -1 has been previously shown to induce the ability of the protein kinase to phosphorylate MEK . Affiliation: Department of Medicine, Walther Oncology Center, Indiana University School of Medicine, Indianapolis 46202, USA . Title: Rapid phosphorylation of Ets-2 accompanies mitogen-activated protein kinase activation and the induction of heparin-binding epidermal growth factor gene expression by oncogenic Raf -1 . PMID: 9111309 Related Articles Authors: McCarthy, S A , et.al. Journal: Mol Cell Biol , Vol. 17 (5): 2401-12 , 1997 Snippet: Heparin-binding epidermal growth factor ( HB - EGF ) gene transcription is rapidly activated in NIH 3T3 cells transformed by oncogenic Ras and Raf and mediates the autocrine activation of the c- Jun N-terminal kinases (JNKs) observed in these cells. Affiliation: Department of Cell Signaling, DNAX Research Institute, Palo Alto , California 94304, USA .
http://www.sciencenet.cn/htmlpaper/20099181121156717343.shtm?id=7343 肝脏疾病相关蛋白质结构与功能研究 9月15日，癌症研究方面的著名期刊《癌症研究》（ Cancer Research ）以封面文章的形式发表了中科院生物物理研究所刘志杰课题组在肝脏疾病相关蛋白质结构与功能研究方面的最新成果。该论文的标题为通过N10取代的叶酸类似物抑制人源5,10-次甲基四氢叶酸合成酶的结构基础。 据悉，叶酸依赖型单碳代谢途径与一些重要的生命活动密切相关，如嘌呤、胸苷和氨基酸代谢等，对细胞的增殖和分化有着重要的调控作用。该代谢途径中的许多催化酶是癌症化疗和其它代谢类疾病的重要靶标，目前市场上已有多种以该代谢途径中的催化酶为靶标的药物用于临床。人源5,10-次甲基四氢叶酸合成酶(Homo sapiens 5,10-methenyltetrahydrofolate synthetase 简称hMTHFS，酶学分类名：EC 6.3.3.2)位于单碳代谢途径的起始点，对代谢途径下游单碳代谢的调控非常重要。针对癌症引起的基因组甲基化异常、DNA和RNA的完整性、DNA的修复能力等，hMTHFS都是一个非常关键的调控位点。因此，hMTHFS也是一个极具潜力的药物靶点。 由于长期以来缺乏hMTHFS的三维结构，人们对其催化和调控的分子机制缺乏深入的了解，以hMTHFS为靶标的药物研发也进展缓慢。刘志杰课题组的该项研究工作报道了该催化酶的四种不同的复合物模型，其中包括hMTHFS-ATP-底物的反应中间态和产物的结构，首次向人们揭示了hMTHFS催化反应活性位点的组成、参与催化反应的重要氨基酸以及催化反应的详细过程。该项研究成果为后续的基于结构的药物设计提供了宝贵的结构信息，为癌症化疗和代谢疾病治疗的新药研制奠定了基础。 该项工作主要由博士后武栋完成，张荣光研究员亦参与了部分研究工作。该研究课题得到了国家自然科学基金委、科技部、卫生部和中国科学院的资助。（来源：中科院生物物理研究所） 更多阅读 《癌症研究》发表论文摘要（英文） http://cancerres.aacrjournals.org/cgi/content/abstract/69/18/7294?maxtoshow=HITS=10hits=10RESULTFORMAT=author1=zhijie+liusearchid=1FIRSTINDEX=0resourcetype=HWCIT Cancer Research 69, 7294, September 15, 2009. Published Online First September 8, 2009; doi: 10.1158/0008-5472.CAN-09-1927 2009 American Association for Cancer Research Experimental Therapeutics, Molecular Targets, and Chemical Biology Structural Basis for the Inhibition of Human 5,10-Methenyltetrahydrofolate Synthetase by N10-Substituted Folate Analogues Dong Wu 1 , Yang Li 1 , Gaojie Song 1 , Chongyun Cheng 1 , Rongguang Zhang 2 , Andrzej Joachimiak 2 , Neil Shaw 1 and Zhi-Jie Liu 1 1 National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China and 2 Structural Biology Center, Argonne National Laboratory, Argonne, Illinois Requests for reprints: Zhi-Jie Liu or Neil Shaw, National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China. Phone: 86-10-64857988; Fax: 86-10-64888426; E-mail: zjliu@ibp.ac.cn
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