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Resistance to ERK1/2 pathway inhibitors;sweet spots,fitness deficits and drug addiction

Cancer Drug Resistance 2019年第2期2卷 365-380页

作者： Matthew J.Sale Kathryn Balmanno Simon J.Cook Signalling Programme The Babraham InstituteBabraham Research CampusCambridge CB223ATUK

MEK1/2 inhibitors are clinically approved for the treatment of BRAF-mutant melanoma,where they are used in combination with BRAF inhibitors,and are undergoing evaluation in other *** resistance to MEK1/2 inhibitors,including selumetinib(AZD6244/ARRY-142866),can arise through amplification of BRAF^(V600E) or KRAS^(G13D) to reinstate ERK1/2 *** have found that BRAF^(V600E) amplification and selumetinib resistance are fully reversible following drug *** is because resistant cells with BRAF^(V600E) amplification become addicted to selumetinib to maintain a precise level of ERK1/2 signalling(2%-3%of total ERK1/2 active),that is optimal for cell proliferation and *** withdrawal drives ERK1/2 activation outside of this critical“sweet spot”(~20%-30%of ERK1/2 active)resulting in a p57^(KIP2)-dependent G1 cell cycle arrest and senescence or expression of NOXA and cell death with features of autophagy;these terminal responses select against cells with amplified BRAF^(V600E).ERK1/2-dependent p57^(KIP2) expression is required for loss of BRAF^(V600E) amplification and determines the rate of reversal of selumetinib *** of selumetinib-resistant cells with BRAF^(V600E) amplification as tumour xenografts also requires the presence of selumetinib to“clamp”ERK1/2 activity within the sweet ***,BRAF^(V600E) amplification confers a selective disadvantage or“fitness deficit”during drug withdrawal,providing a rationale for intermittent dosing to forestall ***,selumetinib resistance driven by KRAS^(G13D) amplification/upregulation is not *** these cells ERK1/2 reactivation does not inhibit proliferation but drives a ZEB1-dependent epithelial-to-mesenchymal transition that increases cell motility and promotes resistance to traditional chemotherapy *** results reveal that the emergence of drug-addicted,MEKi-resistant cells,and the opportunity this may afford for intermittent dosing

关键词： BRAF CDKN1C/p57^(KIP2) EMT ERK KRAS MEK MEK inhibitor resistance selumetinib

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Supramolecular organization of the sperm plasma membrane during maturation and capacitation

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Asian Journal of Andrology 2007年第4期9卷 438-444页

作者： Roy Jones Peter S. James Liz Howes Andreas Bruckbauer David Klenerman the babraham institute Cambridge CB2 4AT UK Department of Chemistry University of Cambridge Cambridge CB2 1EW UK

Aim： In the present study, a variety of high resolution microscopy techniques were used to visualize the organization and motion of lipids and proteins in the sperm＇s plasma membrane. We have addressed questions such as the presence of diffusion barriers, confinement of molecules to specific surface domains, polarized diffusion and the role of cholesterol in regulating lipid rafts and signal transduction during capacitation. Methods： Atomic force microscopy identified a novel region （EqSS） within the equatorial segment of bovine, porcine and ovine spermatozoa that was enriched in constitutively phosphorylated proteins. The EqSS was assembled during epididymal maturation. Fluorescence imaging techniques were then used to follow molecular diffusion on the sperm head. Results： Single lipid molecules were freely exchangeable throughout the plasma membrane and showed no evidence for confinement within domains. Large lipid aggregates, however, did not cross over the boundary between the post-acrosome and equatorial segment suggesting the presence of a molecular filter between these two domains. Conclusion： A small reduction in membrane cholesterol enlarges or increases lipid rafts concomitant with phosphorylation of intracellular proteins. Excessive removal of cholesterol, however, disorganizes rafts with a cessation of phosphorylation. These techniques are forcing a revision of long-held views on how lipids and proteins in sperm membranes are assembled into larger complexes that mediate recognition and fusion with the egg. （Asian JAndrol 2007 July; 9： 438-444）

关键词： cholesterol lipid rafts single molecules sperm membranes

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ApoB-containing lipoproteins promote infectivity of chlamydial species in human hepatoma cell line

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World Journal of Hepatology 2010年第2期2卷 74-80页

作者： Yuriy K Bashmakov Nailia A Zigangirova Alexander L Gintzburg Petr A Bortsov Ivan M Petyaev Cambridge Theranostics Ltd Babraham Research CampusBabrahamCambridgeCB2 4ATUnited Kingdom Gamaleya institute for Epidemiology and Microbiology RAMS 18 Gamaleya Str.Moscow 123098Russia

AIM:To evaluate the direct binding of two main chlamydial biovars(*** and ***) to plasma lipoproteins and its effect on chlamydial infection rate in human hepatoma cell line(HepG2 cells). METHODS:Murine plasma lipoproteins were fractionated and isolated using fast-performance liquid chromatography(FPLC),spotted on nitrocellulose membrane and incubated with chlamydial suspensions. Direct binding of chlamydial particles to lipoprotein fractions has been studied using lipopolysaccharide-specific antibodies in immuno-dot blot binding assay and immunoprecipitation *** protocol as well as flow cytometry analysis have been employed to study the infectivity rate of chlamydial species in HepG2 cells. RESULTS:Elementary bodies of both *** and *** bind ApoB-containing fractions of plasma *** binding becomes stronger when heat-denatured FPLC fractions are used, suggesting a primary role of apolipoproteins in interaction between chlamydial particle and lipoprotein. Both chlamydial biovars efficiently propagate in human hepatoma cell line-HepG2 cells even in serum free conditions forming late-stage inclusion bodies and releasing extracellular elementary *** of *** and *** with native ApoB-containing lipoproteins enhances the rate of chlamydial infection in HepG2 ***:A productive infection caused by C. trachomatis and *** may take place in human-derived hepatocytes revealing hepatic cells as possible target in chlamydial *** results may suggest the participation of lipoprotein receptors in the mechanism of attachment and/or entry of chlamydial particles into target cells.

关键词： ApoB-containing lipoproteins Chlamydial trachomatis Chlamydial pneumoniae Human hepatoma cell line Liver infection

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The RNA binding proteins TIA1 and TIAL1 promote Mcl1 mRNA translation to protect germinal center responses from apoptosis

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Cellular & Molecular Immunology 2023年第9期20卷 1063-1076页

作者： Ines COsma-Garcia Mailys Mouysset Dunja Capitan-Sobrino Yann Aubert Martin Turner Manuel D.Diaz-Muñoz institute for Infectious and Inflammatory Diseases(INFINITy) Inserm UMR1291CNRS UMR5051University Paul SabatierCHU PurpanToulouse 31024France Immunology Program The Babraham InstituteCambridgeUK

Germinal centers(GCs)are essential for the establishment of long-lasting antibody *** B cells rely on post-transcriptional RNA mechanisms to translate activation-associated transcriptional programs into functional changes in the cell ***,the critical proteins driving these key mechanisms are still ***,we show that the RNA binding proteins TIA1 and TIAL1 are required for the generation of long-lasting GC ***1-and TIAL1-deficient GC B cells fail to undergo antigen-mediated positive selection,expansion and differentiation into B-cell clones producing high-affinity ***,TIA1 and TIAL1 control the transcriptional identity of dark-and light-zone GC B cells and enable timely expression of the prosurvival molecule ***,we demonstrate here that TIA1 and TIAL1 are key players in the post-transcriptional program that selects high-affinity antigen-specific GC B cells.

关键词： Adaptive immunity Germinal centers Post-transcriptional gene regulation RNA binding proteins Cell identity Apoptosis/10.1038/s41423-023-01063-4

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Cloned goats (Gapra hircus) from foetal fibroblast cell lines

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Chinese Science Bulletin 2000年第1期45卷 34-38页

作者： WANG Yuge ZOU Xiangang LIU Jie ZHANG Jingpu ZHANG Xuechen LAO Weide DU Miao CHENG Guoxing CHENG Yong CHEN Jianquan ZHANG Suolin XU Shaofu institute of Developmental Biology Chinese Academy of SciencesBeijing 100080China College of Animal Sciences and Veterinary Yangzhou UniversityYangzhou 225001China the babraham institute Cambridge CB2 4ATUK

Mammalian cloning has been one of the most active research topics in the world. Cioning with in vitro culured foetal fibroblast cells, in comparison with embryonic cells, can be used not only to theoretically study the embryonic or cellular development and differentiation in mammals, but also to utilize the unlimited fibroblast cells to produce large numbers of clonings. The preliminary results are as follows: (i) The division and development of the cloned embryos with embryonic donor cells and goat foetal fibroblast donor cells were 55%, 77% and 35%, 31%, respectively. There is no significant statistical difference between them. (? These studies result in the birth of two cloned goats derived from two 30-day foetal fibroblast celi lines, which are the first cloned mammals from somatic cells in China. This project has established a technological data base for the furture research on adult mammalian somatic cloning and nucleocytoplasmic interactions in animal development, and a novel technique for the

关键词： goat (Gapra hircus) foetus fibroblast cloning total-potentiality.

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cDNA CLONING OF RAT 2B1 ANTIGEN;A SPERM SURFACE GLYCOPROTEIN IMPLICATED IN ZONA PELLUCIDA BINDING.

cDNA CLONING OF RAT 2B1 ANTIGEN;A SPERM SURFACE GLYCOPROTEIN...

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第二次北京生育调节国际学术研讨会

作者： Alicia Ma Roy Jones Len Hall babraham institute CambridgeUK. Dept.of Biochemistry BristolUK University of Bristol

＜正＞The rat sperm surface 2B1 antigen has been proposed to play a key role in sperm adhesion to the zona *** have shown that rat 2B1 is synthesised in the testis as a precursor glycoprotein which subsequently undergoes processing to a lower molecular weight form within the epididymis. 2B1 antigen also actively migrates from its location on the tail to the acrosomal region during in vitro capacitation.

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由成年转基因山羊体细胞而来的克隆山羊

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生物工程学报 2002年第1期18卷 79-83页

作者：成勇王玉阁罗金平沈玉杨跃飞鞠辉明邹贤刚徐少甫劳为德杜淼扬州大学畜牧兽医学院扬州225009 中国科学院发育生物学研究所北京100080 the babraham institute

在已经获得的乳腺特异性表达人促红细胞生成素 (rhEPO)成年转基因山羊 (Caprahircus)的基础上 ,取其耳尖成纤维细胞和卵巢颗粒细胞 ,进行体外传代培养 ,然后将这种培养的转基因山羊的体细胞移入去核的处于第Ⅱ次减数分裂中期的卵母细胞... 详细信息

在已经获得的乳腺特异性表达人促红细胞生成素 (rhEPO)成年转基因山羊 (Caprahircus)的基础上 ,取其耳尖成纤维细胞和卵巢颗粒细胞 ,进行体外传代培养 ,然后将这种培养的转基因山羊的体细胞移入去核的处于第Ⅱ次减数分裂中期的卵母细胞中 ,并进行电融合 ,构建重构胚胎 ,重构胚胎在体内培养 6d ,再将发育至囊胚或桑椹胚的重构胚胎移入同步情期的寄母羊子宫内。结果 ,有 2只寄母羊妊娠并最终产下 2只成活的克隆山羊。她们分别来自同一成年母羊的耳尖成纤维细胞和卵巢颗粒细胞。克隆羊经PCR RFLP图谱分析显示 :以克隆羊组织DNA为模板的PCR产物与相应的提供体细胞的基因羊的PCR产物的酶切图谱完全一致 ;并且经PCR对外源hEPO基因检测表明 2只克隆山羊均携带hEPO外源基因。

关键词：成年转基因山羊体细胞克隆山羊

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含有His 5基因用于酵母人工染色体重组筛选的置换型载体的构建

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农业生物技术学报 2004年第2期12卷 170-174页

作者：任立明,邹贤刚,Marianne Brüggemann 中国农业大学农业生物技术国家实验室 Laboratory of Genetic and Developmental Immunology the babraham institute Cambridge CB2 4AT UK Laboratory of Genetic and Developmental Immunology the babraham institute Cambridge CB2 4AT UK 北京100094

人工酵母染色体(YAC)可以克隆和分析大片段的染色体DNA,并且可以分离那些在大肠杆菌(Escherichiacoli)中不可能得到的序列。实验将His5基因插入到一个Ura3基因的中间,构建了一个新的质粒pLRH33,从而打断了Ura3 基因使之不能表达。利用H... 详细信息

人工酵母染色体(YAC)可以克隆和分析大片段的染色体DNA,并且可以分离那些在大肠杆菌(Escherichiacoli)中不可能得到的序列。实验将His5基因插入到一个Ura3基因的中间,构建了一个新的质粒pLRH33,从而打断了Ura3 基因使之不能表达。利用His5基因两端各留下的部分Ura3基因片段,同源重组到YAC臂上原有的Ura3基因中,使重组后的YAC的标记性状从Ura+ His- 变成了His+ Ura-。用质粒pLRH33的5.5 kb线性片段以一定比例和需要重组到YAC上的目的基因pBAC300的50 kb片段相混合,同时作酵母菌转化,在His- Ura+培养基上得到大量带His5基因的阳性克隆。在检测的1 200个克隆中,有250个目的基因阳性克隆,占受检克隆的22.5%。表明质粒pLRH33可以有效地用作YAC重组的筛选标记。

关键词：酵母人工染色体(YAC) His5基因 Ura3基因同源重组置换型载体

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The role of prostaglandins in regulating vascular smooth muscle cell sur-vival par

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Cell Research 2002年第Z1期 303-303页

作者： TEREZACINDROVA,JEREMYSKEPPER,LYNDASELLERSA Anatomy University of Cambridge Cambridge CB2 IPD UK 3 Anatomy University of Cambridge Cambridge CB2 IPD UK 3 Department of Neurobiology babraham institute babraham Cambridge CB2 4AT UK

Abnormal proliferation of vascular smooth muscle cells (VSMCs) is a major causative factor in atherosclerosis. Prostaglandins, secreted by endothelial cells, are reported to attenuate VSMC proliferation, but the mechanism through which this response is mediated is poorly denned. Here, the effect of prostaglandin receptor-selective agonists on the activity status of ERK and PKC, both known to modulate proliferative responses, was determined. The effect of the prostacyclin mimetic, iloprost, at inducing apoptosis was also investigated. VSMCs in culture were shown to express proteins that were detected by antibodies selective

关键词： cell The role of prostaglandins in regulating vascular smooth muscle cell sur-vival par

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由成年转基因山羊(Capra hircus)体细胞而来的克隆山羊

由成年转基因山羊(Capra hircus)体细胞而来的克隆山羊

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中国生物工程学会第三次全国会员代表大会暨学术讨论会

作者：成勇王玉阁罗金平沈玉杨跃飞唐慧林鞠辉明耿世忠邹贤刚徐少甫张旭晨劳为德杜淼扬州大学畜牧兽医学院中国科学院发育生物学研究所 the babraham institute babraham Cambridge CB2 4AT UK

在已经获得的乳腺特异性表达人促红细胞生成素(rhEPO)成年转基因山羊的基础上,取其耳尖成纤维细胞和卵巢颗粒细胞,进行体外传代培养。然后将这种培养的转基因山羊的体细胞移入去核的处于第Ⅱ次减数分裂中期的卵母细胞中,构建重构胚胎。...

在已经获得的乳腺特异性表达人促红细胞生成素(rhEPO)成年转基因山羊的基础上,取其耳尖成纤维细胞和卵巢颗粒细胞,进行体外传代培养。然后将这种培养的转基因山羊的体细胞移入去核的处于第Ⅱ次减数分裂中期的卵母细胞中,构建重构胚胎。重构胚胎在体内培养6天,再将发育至囊胚或桑椹胚的重构胚胎移入同步情期的寄母羊子宫内。结果,有两只寄母羊妊娠并最终产下两只成活的克隆山羊。她们分别来自同一成年母羊的耳尖成纤维细胞和卵巢颗粒细胞。克隆羊经PCR-RFLP图谱分析显示:以克隆羊组织DNA为模板的PCR产

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