企业邮箱
天下生命科学前沿动态周报（五十三）
（8.15-8.21/2011）
太阳集团官网国际集团:陶国新
主要内容：展现基因组不稳固性的新机制；肿瘤细胞群的平衡可由其恣意亚群细胞恢复；线粒体中的血管主要素系统；Fh突变导致的新的能量代谢方法；应用药物重新定位开发新药；干细胞和癌细胞调控的新熟悉 。
焦点动态：肿瘤细胞群的平衡可由其恣意亚群细胞恢复 。
1. 展现基因组不稳固性的新机制
【动态】
由于复制速率远快于转录速率，复制体和RNA聚合酶之间不可阻止地会频仍泛起同向碰撞 。美国科学家在大肠杆菌中发明此类碰撞的效果依赖于转录延伸复合物（ECs）的生产状态 。与回溯的ECs的同向碰撞导致DNA双链断裂，而正面相撞不会 。他们提出了一个机械模子予以诠释 。进一步研究显示细菌使用多种战略来阻止复制体与回溯的RNA聚合酶爆发碰撞，最常见的战略就是通过翻译避免RNA聚合酶回溯 。若是作废翻译，DNA双链断裂被延伸因子（抑制回溯或重新激活回溯的ECs）所抑制 。最终，终止因子也通已往除被抑制的ECs对基因组稳固性作出孝顺 。其研究效果确立了RNA聚合酶的回溯是染色体完整性的内在危险因素，提醒了活性核糖体和其他的抗回溯机制是基因组稳固性的维持因素 。
【点评】
该研究发明了大肠杆菌通常爆发染色体断裂的细胞机制，进一步探明晰基因组不稳固性的缘故原由 。
【参考论文】
Cell, Volume 146, Issue 4, 533-543, 19 August 2011 DOI:10.1016/j.cell.2011.07.034
Linking RNA Polymerase Backtracking to Genome Instability in E. coli
Dipak Dutta, Konstantin Shatalin, Vitaly Epshtein, et al.
Frequent codirectional collisions between the replisome and RNA polymerase (RNAP) are inevitable because the rate of replication is much faster than that of transcription. Here we show that, in E. coli, the outcome of such collisions depends on the productive state of transcription elongation complexes (ECs). Codirectional collisions with backtracked (arrested) ECs lead to DNA double-strand breaks (DSBs), whereas head-on collisions do not. A mechanistic model is proposed to explain backtracking-mediated DSBs. We further show that bacteria employ various strategies to avoid replisome collisions with backtracked RNAP, the most general of which is translation that prevents RNAP backtracking. If translation is abrogated, DSBs are suppressed by elongation factors that either prevent backtracking or reactivate backtracked ECs. Finally, termination factors also contribute to genomic stability by removing arrested ECs. Our results establish RNAP backtracking as the intrinsic hazard to chromosomal integrity and implicate active ribosomes and other anti-backtracking mechanisms in genome maintenance.
2. 肿瘤细胞群的平衡可由其恣意亚群细胞恢复
【动态】
在单个的肿瘤中癌细胞经常保存具有差别功效属性的差别表型 。癌细胞群通常在差别状态的细胞组成上体现出奇异的平衡，其爆发气制还很不明晰 。美国科学家研究了人乳腺癌细胞系中表型比例的动态转变 。发明纯化出来的特定表型的细胞亚群随时间推移又回到原来平衡态 。这些视察效果可以用Markov模子诠释，即细胞在差别状态间随机转变 。这一模子展望一，确定特定条件，随时间推移任何亚群细胞都会回到平衡态表型比例 。展望二，乳腺癌干细胞样细胞从非干细胞样细胞全新爆发 。这些发明有益于我们明确肿瘤异质性并展现单个细胞行为的随机性增进了癌细胞群的表型平衡 。
【点评】
统一肿瘤中癌细胞并非都是一样的，更像一个重大社会，由具有差别功效的差别类型癌细胞形成奇异的平衡 。而肿瘤干细胞也可能是有由其他类型癌细胞转变来的 。
【参考论文】
Cell, 2011; 146 (4): 633-644 DOI: 10.1016/j.cell.2011.07.026
Stochastic State Transitions Give Rise to Phenotypic Equilibrium in Populations of Cancer Cells
Piyush B. Gupta, Christine M. Fillmore, Guozhi Jiang, et al.
Cancer cells within individual tumors often exist in distinct phenotypic states that differ in functional attributes. While cancer cell populations typically display distinctive equilibria in the proportion of cells in various states, the mechanisms by which this occurs are poorly understood. Here, we study the dynamics of phenotypic proportions in human breast cancer cell lines. We show that subpopulations of cells purified for a given phenotypic state return towards equilibrium proportions over time. These observations can be explained by a Markov model in which cells transition stochastically between states. A prediction of this model is that, given certain conditions, any subpopulation of cells will return to equilibrium phenotypic proportions over time. A second prediction is that breast cancer stem-like cells arise de novo from non-stem-like cells. These findings contribute to our understanding of cancer heterogeneity and reveal how stochasticity in single-cell behaviors promotes phenotypic equilibrium in populations of cancer cells.
3. 线粒体中的血管主要素系统
【动态】
肾素-血管主要素（Ang）系统通过Ang II 1型和2型受体调理多种心理功效 。以往的研究提醒在激活外貌膜Ang受体时细胞内的Ang II池可能以自渗透模式释放 。作为选择，提出了一种细胞内的肾素-血管主要素系统，主要焦点在核Ang受体 。美国科学家研究了线粒体的血管主要素系统，发明功效性的Ang II 2型受体泛起在线粒体内膜上与内源性的Ang定位相同 。他们证实晰线粒体的血管主要素系统的激活是藕连于线粒体一氧化氮的爆发并能调理呼吸作用 。别的，他们还提出了线粒体血管主要素受体表达中年岁相关的转变的证据，即恒久举行Ang II 1型受体抑制剂氯沙坦治疗可以逆转升高的线粒体Ang II 1型受体和降低的2型受体密度 。在人线粒体中保存功效性的血管主要素系统为明确线粒体和慢性疾病状态之间相互作用提供了基� 。⒄瓜至擞糜谟呕吡Ｌ骞πШ惋蕴嗦醮吹穆圆〖绺旱那痹谥瘟瓢械� 。
【点评】
新发明线粒体中保存血管主要素系统，并随年岁而衰减但能用药物逆转 。
【参考论文】
Proceedings of the National Academy of Sciences, 2011; DOI:10.1073/pnas.1101507108
Identification and characterization of a functional mitochondrial angiotensin system
Peter M. Abadir, D. Brian Foster, Michael Crow, et al.
The renin-angiotensin (Ang) system regulates multiple physiological functions through Ang II type 1 and type 2 receptors. Prior studies suggest an intracellular pool of Ang II that may be released in an autocrine manner upon stretch to activate surface membrane Ang receptors. Alternatively, an intracellular renin-Ang system has been proposed, with a primary focus on nuclear Ang receptors. A mitochondrial Ang system has not been previously described. Here we report that functional Ang II type 2 receptors are present on mitochondrial inner membranes and are colocalized with endogenous Ang. We demonstrate that activation of the mitochondrial Ang system is coupled to mitochondrial nitric oxide production and can modulate respiration. In addition, we present evidence of age-related changes in mitochondrial Ang receptor expression, i.e., increased mitochondrial Ang II type 1 receptor and decreased type 2 receptor density that is reversed by chronic treatment with the Ang II type 1 receptor blocker losartan. The presence of a functional Ang system in human mitochondria provides a foundation for understanding the interaction between mitochondria and chronic disease states and reveals potential therapeutic targets for optimizing mitochondrial function and decreasing chronic disease burden with aging.
4. Fh突变导致的新的能量代谢方法
【动态】
延胡索酸水合酶（FH）是三羧酸循环中催化延胡索酸水解为苹果酸的酶 。FH的遗传突变导致遗传性平滑肌瘤病和肾细胞癌 。已经证实FH缺乏会导致延胡索酸积累，在正常氧含量时激活缺氧诱导因子 。然而，迄今没有机制能诠释细胞在没有功效性的三羧酸循环时存活的能力 。一个由多国科学家配合完成的最新研究用去除Fh1的基因刷新老鼠肾细胞团结新开发的这些细胞代谢的盘算模子来展望和实验验证一条始于谷氨酸盐摄取止于胆红素渗透的线性代谢途径 。这一牵涉血红素生物合成和降解的途径，使得Fh1缺陷细胞能够使用累积的三羧酸循环代谢产品并允许线粒体生产部分NADH 。他们展望并确认了以此途径为目的能使Fh1缺陷细胞无法存活而不影响野生型的含有Fh1的细胞 。
【点评】
这一研究说明关闭某些爆发特殊突变改变了能量代谢途径的肾癌细胞的能量工厂可以杀死这些癌细胞而不影响正常细胞 。
【参考论文】
Nature, 2011; DOI:10.1038/nature10363
Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase
Christian Frezza, Liang Zheng, Ori Folger, et al.
Fumarate hydratase (FH) is an enzyme of the tricarboxylic acid cycle (TCA cycle) that catalyses the hydration of fumarate into malate. Germline mutations of FH are responsible for hereditary leiomyomatosis and renal-cell cancer (HLRCC). It has previously been demonstrated that the absence of FH leads to the accumulation of fumarate, which activates hypoxia-inducible factors (HIFs) at normal oxygen tensions. However, so far no mechanism that explains the ability of cells to survive without a functional TCA cycle has been provided. Here we use newly characterized genetically modified kidney mouse cells in which Fh1 has been deleted, and apply a newly developed computer model of the metabolism of these cells to predict and experimentally validate a linear metabolic pathway beginning with glutamine uptake and ending with bilirubin excretion from Fh1-deficient cells. This pathway, which involves the biosynthesis and degradation of haem, enables Fh1-deficient cells to use the accumulated TCA cycle metabolites and permits partial mitochondrial NADH production. We predicted and confirmed that targeting this pathway would render Fh1-deficient cells non-viable, while sparing wild-type Fh1-containing cells. This work goes beyond identifying a metabolic pathway that is induced in Fh1-deficient cells to demonstrate that inhibition of haem oxygenation is synthetically lethal when combined with Fh1 deficiency, providing a new potential target for treating HLRCC patients.
5. 应用药物重新定位开发新药
【动态】
药物重新定位，即将已有药物分子应用到新的顺应症，比古板的药物开发有数种优势，包括更少的开发用度和更短的审批历程 。最新的药物重新定位手艺使用高通量实验要领评价化合物的潜在治疗能力 。美国科学家整合了100种疾病的基因表达丈量值和164种药物分子的基因表达丈量值，形成对这些药物的展望治疗作用 。他们实验验证了一个展望，即抗溃疡药西咪替丁能够治疗肺腺癌，并用异种移植老鼠模子证实晰它的体内体外活性 。
【点评】
通过最先进的盘算模子和生物学信息数据剖析来充分挖掘现有药物分子的治疗作用的潜力不失是一种更有用更经济的新药开发途径 。
【参考论文】
Science Translational Medicine, 2011; 3 (96): 96ra77 DOI:10.1126/scitranslmed.3001318
Discovery and Preclinical Validation of Drug Indications Using Compendia of Public Gene Expression Data
Marina Sirota, Joel T. Dudley, Jeewon Kim, et al.
The application of established drug compounds to new therapeutic indications, known as drug repositioning, offers several advantages over traditional drug development, including reduced development costs and shorter paths to approval. Recent approaches to drug repositioning use high-throughput experimental approaches to assess a compound’s potential therapeutic qualities. Here, we present a systematic computational approach to predict novel therapeutic indications on the basis of comprehensive testing of molecular signatures in drug-disease pairs. We integrated gene expression measurements from 100 diseases and gene expression measurements on 164 drug compounds, yielding predicted therapeutic potentials for these drugs. We recovered many known drug and disease relationships using computationally derived therapeutic potentials and also predict many new indications for these 164 drugs. We experimentally validated a prediction for the antiulcer drug cimetidine as a candidate therapeutic in the treatment of lung adenocarcinoma, and demonstrate its efficacy both in vitro and in vivo using mouse xenograft models. This computational method provides a systematic approach for repositioning established drugs to treat a wide range of human diseases.
6. 干细胞和癌细胞调控的新熟悉
【动态】
细胞自我更新或分解的决议源于多种调理网络的整合和相互协调 。Notch 和Wnt/β-catenin 信号经常交汇于干细胞和祖细胞并相互转录调理 。当细胞履历分解的各阶段时，每种途径的生物学效应经常依赖于情形和时机 。美国科学家最近发明在干细胞和结肠癌细胞中膜团结的Notch经常与未磷酸化的（活性的）β-catenin有物理性的联系并负向调理活性β-catenin卵白在翻译后的群集 。Notch依赖性的β-catenin卵白的调理不需要配体加入的Notch与膜解离或者糖原合成酶激酶3β依赖的β-catenin消除复合体的活性，但它确实需要内吞噬转接卵白Numb和溶酶体活性 。
【点评】
关于干细胞和癌细胞更深入的相识，可能最终会导致调理细胞生长情形来控制细胞的运气 。
【参考论文】
Nature Cell Biology, 2011; DOI: 10.1038/ncb2313
Notch post-translationally regulates β-catenin protein in stem and progenitor cells
Chulan Kwon, Paul Cheng, Isabelle N. King, et al.
Cellular decisions of self-renewal or differentiation arise from integration and reciprocal titration of numerous regulatory networks. Notch and Wnt/β-catenin signalling often intersect in stem and progenitor cells and regulate each other transcriptionally. The biological outcome of signalling through each pathway often depends on the context and timing as cells progress through stages of differentiation. Here, we show that membrane-bound Notch physically associates with unphosphorylated (active) β-catenin in stem and colon cancer cells and negatively regulates post-translational accumulation of active β-catenin protein. Notch-dependent regulation of β-catenin protein did not require ligand-dependent membrane cleavage of Notch or the glycogen synthase kinase- 3β-dependent activity of the β-catenin destruction complex. It did, however, require the endocytic adaptor protein Numb and lysosomal activity. This study reveals a previously unrecognized function of Notch in negatively titrating active β-catenin protein levels in stem and progenitor cells.