（11.21-11.27/2011）
恒峰g22国际集团:陶国新 

　　重要内容：指（趾）的形成显示了“垃圾基因”的作用；糖尿病药降低患癌风险；细胞移植受体的免疫系统节造移植干细胞的再生；线虫钻研揭示伤口愈合反映的奥秘；维持Sip2的乙；⒏榻湍甘倜；发现端粒酶耽搁端粒的关键分子开关。

　　焦点动态：发现端粒酶耽搁端粒的关键分子开关。

1. 指（趾）的形成显示了“垃圾基因”的作用
【动态】
　　指（趾）头的进化是四足动物成功的必要步骤，在指（趾）头发育的关键成分中，Hoxd基因受到协调节造，援手治理成长和模式。瑞士、荷兰和德国的科学家通过探查发育中的手脚的三位机关确定了与这些基因有关的肢端调节位点。该步骤结合体内删除特定的调节区，显示基因簇的活性部位与数个加强子样的序列接触。这些序列分散在邻近的所谓垃圾基因序列中，各自对预期的指（趾）的Hox基因转录做出定量或定性的贡献。他们提闻名为“调节列岛”的基因系统，提供一种遗传矫捷性可能部门支持四足动物中指（趾）数量和状态的多样性以及适应剧烈变动的能力。

【点评】
　　该钻研批注在已经错以为没有任何作用的垃圾基因序列中的一些序列可能相互结合，调节掌管形成指（趾）头的基因的作用。这样的了局批瞩目前人类对基因的钻研仍未成熟，尤其是对职能基因的作用机造还有好多工作要做。

【参考论文】
Cell, 2011; 147 (5): 1132 DOI: 10.1016/j.cell.2011.10.023 
A Regulatory Archipelago Controls Hox Genes Transcription in Digits
Thomas Montavon, Natalia Soshnikova, Bénédicte Mascrez, et al.
Highlights
Hox genes active in digits integrate the input of multiple regulatory elements
The global regulatory architecture of the HoxD locus involves flanking gene deserts
Alterations in this regulatory structure may fine tune digital morphology in tetrapods
Summary
The evolution of digits was an essential step in the success of tetrapods. Among the key players, Hoxd genes are coordinately regulated in developing digits, where they help organize growth and patterns. We identified the distal regulatory sites associated with these genes by probing the three-dimensional architecture of this regulatory unit in developing limbs. This approach, combined with in vivo deletions of distinct regulatory regions, revealed that the active part of the gene cluster contacts several enhancer-like sequences. These elements are dispersed throughout the nearby gene desert, and each contributes either quantitatively or qualitatively to Hox gene transcription in presumptive digits. We propose that this genetic system, which we call a regulatory archipelago, provides an inherent flexibility that may partly underlie the diversity in number and morphology of digits across tetrapods, as well as their resilience to drastic variations.
 
2. 糖尿病药降低患癌风险
【动态】
　　一种廉价的2型糖尿病医治药物，抑造糖异生基因转录的二甲双胍证明可能预防好多天然某人为合成的化合物刺激乳腺癌细胞成长，降低糖尿病有关肿瘤的风险。最近，肿瘤干细胞被以为是掌管维持肿瘤成长，抵抗医治。韩国和美国科学家为了验证二甲双胍可能削减乳腺癌风险的如果，将成长于代表人体乳腺癌干细胞群的三维乳球体中的MCF-7人体乳腺癌细胞系在有/无非细胞毒性浓度的二甲双胍存鄙人用各类已知的和可能的乳腺癌诱发剂处置，OCT4表白作为肿瘤干细胞的标志，测定这些细胞的数量和大幼。了局批注100nM的TCDD和10µM的双酚A像10µM的雌激素一样增长了三维乳球体的数量和大幼。通过检测标志物OCT4，这些致癌物的刺激与OCT4表白增多有关。另一方面，1mM和10mM的二甲双胍可能大大削减三维乳球体的数量和大幼。了局还显示二甲双胍可能削减雌激素和TCDD诱生的三维乳球体中OCT4的表白，但在双酚A诱生的三维乳球体中则不能，批注双酚A对人体乳腺癌细胞有分歧的作用机造。另表，这些了局支持使用三维人体乳腺癌干细胞作为一种伎俩筛选潜在的人体乳腺癌致癌物以及化学预防和医治剂。

【点评】
　　该钻研发现了廉价的糖尿病药物二甲双胍可能通过抑造雌激素受体介导的癌基因OCT4的表白，削减人体乳腺癌干细胞的自我复造。同时为乳腺癌的防治和二甲双胍的老药新用提供了新的可能。

【参考论文】
PLoS ONE, 2011; 6 (11): e28068 DOI: 10.1371/journal.pone.0028068 
Metformin Represses Self-Renewal of the Human Breast Carcinoma Stem Cells via Inhibition of Estrogen Receptor-Mediated OCT4 Expression
Ji-Won Jung, Sang-Bum Park, Soo-Jin Lee, et al.
Metformin, a Type II diabetic treatment drug, which inhibits transcription of gluconeogenesis genes, has recently been shown to lower the risk of some diabetes-related tumors, including breast cancer. Recently, “cancer stem cells” have been demonstrated to sustain the growth of tumors and are resistant to therapy. To test the hypothesis that metformin might be reducing the risk to breast cancers, the human breast carcinoma cell line, MCF-7, grown in 3-dimensional mammospheres which represent human breast cancer stem cell population, were treated with various known and suspected breast cancer chemicals with and without non-cytotoxic concentrations of metformin. Using OCT4 expression as a marker for the cancer stem cells, the number and size were measured in these cells. Results demonstrated that TCDD (100 nM) and bisphenol A (10 µM) increased the number and size of the mammospheres, as did estrogen (10 nM E2). By monitoring a cancer stem cell marker, OCT4, the stimulation by these chemicals was correlated with the increased expression of OCT4. On the other hand, metformin at 1 and 10 mM concentration dramatically reduced the size and number of mammospheres. Results also demonstrated the metformin reduced the expression of OCT4 in E2 & TCDD mammospheres but not in the bisphenol A mammospheres, suggesting different mechanisms of action of the bisphenol A on human breast carcinoma cells. In addition, these results support the use of 3-dimensional human breast cancer stem cells as a means to screen for potential human breast tumor promoters and breast chemopreventive and chemotherapeutic agents.

3. 细胞移植受体的免疫系统节造移植干细胞的再生
【动态】
　　受体的T淋巴细胞通过IFN-γ和TNF-α节造基于间充质干细胞的组织再生。在组织重建中基于干细胞的再生医学是一种很有但愿的步骤。南加大的美国科学家最近报路了促炎T细胞抑造表源骨髓间充质干细胞（BMMSCs）疏导骨头建复的能力。这一抑造作用来自滋扰素γ（IFN-γ）诱导的干细胞中runt有关转录因子2（Runx-2）蹊径下和谐肿瘤坏死因子α（TNF-α）信号的加强。他们还发现，通过抑造核因子κB (NF-κB)，TNF-α将BMMSCs中IFN-γ激活的，非凋亡状态的TNF受体超家族成员6（Fas）信号转变为细胞凋亡蛋白酶3和8有关的促凋亡级联反映信号，导致这些细胞凋亡。相反地，通过全身输入Foxp3(+)调节性T细胞或部门给药阿司匹林来削减IFN-γ 和 TNF-α的浓度，显著地推进了C57BL/6老鼠基于BMMSC的骨骼再生和颅骨缺损的建复。这些数据合起来批注前所未知的受体T细胞在基于BMMSC的组织工程中的作用。

【点评】
　　该钻研批注基于干细胞的再生医学钻研必要关注机体自身的免疫系统对组织再生的调控，干细胞钻研和再生医学的突破离不开干细胞所处机体环境的钻研。

【参考论文】
Nature Medicine, 2011 DOI: 10.1038/nm.254 
Mesenchymal stem cell-based tissue regeneration is governed by recipient T lymphocytes via IFN-γ and TNF-α
Yi Liu, Lei Wang, Takashi Kikuiri, et al.
Stem cell-based regenerative medicine is a promising approach in tissue reconstruction. Here we show that proinflammatory T cells inhibit the ability of exogenously added bone marrow mesenchymal stem cells (BMMSCs) to mediate bone repair. This inhibition is due to interferon γ (IFN-γ)-induced downregulation of the runt-related transcription factor 2 (Runx-2) pathway and enhancement of tumor necrosis factor α (TNF-α) signaling in the stem cells. We also found that, through inhibition of nuclear factor κB (NF-κB), TNF-α converts the signaling of the IFN-γ-activated, nonapoptotic form of TNF receptor superfamily member 6 (Fas) in BMMSCs to a caspase 3- and caspase 8-associated proapoptotic cascade, resulting in the apoptosis of these cells. Conversely, reduction of IFN-γ and TNF-α concentrations by systemic infusion of Foxp3(+) regulatory T cells, or by local administration of aspirin, markedly improved BMMSC-based bone regeneration and calvarial defect repair in C57BL/6 mice. These data collectively show a previously unrecognized role of recipient T cells in BMMSC-based tissue engineering.

4. 线虫钻研揭示伤口愈合反映的奥秘
【动态】
　　在严格的环境中生计，动物必须可能建复皮肤创伤，然而体内启动创伤建复的信号蹊径还不了然。在线虫中，p38割裂素激活的蛋白激酶（MAPK）级联反映推进应对创伤的先天免疫反映，但不是创伤愈合其他方面所需的。美国科学家为此在线虫表皮中探查了其他的创伤反映信号蹊径。了局批注线虫表皮创伤引发迅速而持续的表皮中钙离子浓度的上升，这是创伤后存活的关键。创伤触发的钙离子增多必要表皮瞬时受体电压通路、melastatin家族（TRPM）通路GTL-2和IP3R刺激的内部贮存池的开释。他们确立了一个表皮信号传导蹊径，蕴含Gαq EGL-30 及其效应器 PLCβ EGL-8。该蹊径失效的话会导致侵害创伤后存活。Gαq-Ca2+蹊径对已知的应对创伤的先天免疫反映不是必须的 ，但会推进肌动蛋白依赖的伤口关合。伤口关合必要Cdc42幼GTP酶和Arp2/3-依赖的肌动蛋白聚合，并被Rho 和非肌肉的肌球蛋白负向调节。他们还发现殒命有关蛋白激酶DAPK-1负向调节伤口关合。

【点评】
　　该钻研批注线虫皮肤创伤会触发钙离子依赖的信号级联反映推进伤口关合，同时伴有危险引起的先天免疫反映。对于意识创伤早期的生化事务和推进创伤愈合钻研有援手。

【参考论文】
Current Biology, 2011; DOI: 10.1016/j.cub.2011.10.050 
A Gαq-Ca2 Signaling Pathway Promotes Actin-Mediated Epidermal Wound Closure in C. elegans
Suhong Xu, Andrew D. Chisholm.
Background
Repair of skin wounds is essential for animals to survive in a harsh environment, yet the signaling pathways initiating wound repair in vivo remain little understood. In Caenorhabditis elegans, a p38 mitogen-activated protein kinase (MAPK) cascade promotes innate immune responses to wounding but is not required for other aspects of wound healing. We therefore set out to identify additional wound response pathways in C. elegans epidermis.
Results
We show here that wounding the adult C. elegans skin triggers a rapid and sustained rise in epidermal Ca2+ that is critical for survival after wounding. The wound-triggered rise in Ca2+ requires the epidermal transient receptor potential channel, melastatin family (TRPM) channel GTL-2 and IP3R-stimulated release from internal stores. We identify an epidermal signal transduction pathway that includes the Gαq EGL-30 and its effector PLCβ EGL-8. Loss of function in this pathway impairs survival after wounding. The Gαq-Ca2+ pathway is not required for known innate immune responses to wounding but instead promotes actin-dependent wound closure. Wound closure requires the Cdc42 small GTPase and Arp2/3-dependent actin polymerization and is negatively regulated by Rho and nonmuscle myosin. Finally, we show that the death-associated protein kinase DAPK-1 acts as a negative regulator of wound closure.
Conclusions
Skin wounding in C. elegans triggers a Ca2+-dependent signaling cascade that promotes wound closure, in parallel to the innate immune response to damage. Wound closure requires actin polymerization and is negatively regulated by nonmuscle myosin.

5. 维持Sip2的乙；⒏榻湍甘倜
【动态】
　　蛋白乙；怯跋旌枚嘞赴悦痰闹匾姆牒蠼ㄊ。美国和台湾的科学家最近发现随着细胞变老，单细胞酵母中AMP激活的蛋白激酶Snf1复合物的β调节亚基Sip2的NuA4乙；骷。通过拮抗NuA4乙；泼负蚏pd3脱乙；附谠斓腟ip2乙；忧苛擞隨nf1复合物的催化亚基Snf1的相互作用。Sip2-Snf1相互作用抑造Snf1的活性，削减下游靶点Sch9（Akt/S6K同源物）的磷酸化，最终导致成长变慢但是耽搁了细胞复造的寿命（复造次数）。Sip2乙；抡瘴锔艿挚寡趸沽。他们还发现Sip2乙；目顾ダ献饔貌灰览当砝从蚑ORC1活性。他们提出蛋白乙；-磷酸化连锁反映调节Sch9活性，节造自身的衰老，耽搁酵母滋生的寿命（滋生更多代）。天然酵母的正常滋生寿命是25代，而通过基因工程刷新复原乙；Ыㄊ蔚慕湍缸躺倜锏38代，耽搁了50%。

【点评】
　　在酵母中维持Snf1复合物β调节亚基Sip2的乙；，拥有抗衰老作用。文中尝试了通过基因刷新仿照这一乙；止，达到了耽搁酵母寿命达50%的成效。若是不用刷新基因，通过其他更天然的步骤也能维持Sip2的乙；，可能是抗衰老的重大突破。

【参考论文】
Cell, 2011; 146 (6): 969 DOI: 10.1016/j.cell.2011.07.044
Acetylation of Yeast AMPK Controls Intrinsic Aging Independently of Caloric Restriction
Jin-Ying Lu, Yu-Yi Lin, Jin-Chuan Sheu, et al. 
Acetylation of histone and nonhistone proteins is an important posttranslational modification affecting many cellular processes. Here, we report that NuA4 acetylation of Sip2, a regulatory β subunit of the Snf1 complex (yeast AMP-activated protein kinase), decreases as cells age. Sip2 acetylation, controlled by antagonizing NuA4 acetyltransferase and Rpd3 deacetylase, enhances interaction with Snf1, the catalytic subunit of Snf1 complex. Sip2-Snf1 interaction inhibits Snf1 activity, thus decreasing phosphorylation of a downstream target, Sch9 (homolog of Akt/S6K), and ultimately leading to slower growth but extended replicative life span. Sip2 acetylation mimetics are more resistant to oxidative stress. We further demonstrate that the anti-aging effect of Sip2 acetylation is independent of extrinsic nutrient availability and TORC1 activity. We propose a protein acetylation-phosphorylation cascade that regulates Sch9 activity, controls intrinsic aging, and extends replicative life span in yeast.

6. 发现端粒酶耽搁端粒的关键分子开关
【动态】
　　进化上守旧的端粒包庇蛋白复合物在哺乳动物和裂殖酵母的端粒酶调节中寂仔正面作用也有负面作用。只管哺乳动物细胞的包庇蛋白预防查抄点激酶ATM和ATR在端粒处充分激活DNA危险反映，这些激酶也推进端粒的守护。短缺Tel1（ATM直接同源物）和Rad3（ATR直接同源物）的裂殖酵母细胞无法招募端粒酶到端粒上，无法通过环形染色体存活。但是，还不知路Tel1ATM和Rad3ATR对应的端粒底物。美国科学家最近的钻研批注Tel1ATM和/或Rad3ATR调节的包庇蛋白亚基Ccq1在93号苏氨酸上的磷酸化是端粒酶联系端粒所必须的。另表，端粒酶亚基Est1直接与Ccq1的磷酸化的93号苏氨酸相互作用以保障端粒的守护。包庇蛋白亚基Taz1, Rap1 和 Poz1 (以前已确认的端粒酶抑造剂) 也负向调节 Ccq1磷酸化 。所有这些发现证明Tel1ATM/Rad3ATR依赖的 Ccq1 的93号苏氨酸磷酸化是裂殖酵母守护端粒的关键调节器。

【点评】
　　该钻研进一步阐释了端粒酶蹊径守护端粒长度的机造，对于意识各细胞组分若何协调一致维持端粒的正常职能和寻找预防癌症的步骤有重要意思。

【参考论文】
Nature Structural & Molecular Biology, 2011; DOI: 10.1038/nsmb.2187 
Tel1ATM and Rad3ATR kinases promote Ccq1-Est1 interaction to maintain telomeres in fission yeast
Bettina A Moser, Ya-Ting Chang, Jorgena Kosti, et al.
The evolutionarily conserved shelterin complex has been shown to play both positive and negative roles in telomerase regulation in mammals and fission yeast. Although shelterin prevents the checkpoint kinases ATM and ATR from fully activating DNA damage responses at telomeres in mammalian cells, those kinases also promote telomere maintenance. In fission yeast, cells lacking both Tel1 (ATM ortholog) and Rad3 (ATR ortholog) fail to recruit telomerase to telomeres and survive by circularizing chromosomes. However, the critical telomere substrate(s) of Tel1ATM and Rad3ATR was unknown. Here we show that phosphorylation of the shelterin subunit Ccq1 on Thr93, redundantly mediated by Tel1ATM and/or Rad3ATR, is essential for telomerase association with telomeres. In addition, we show that the telomerase subunit Est1 interacts directly with the phosphorylated Thr93 of Ccq1 to ensure telomere maintenance. The shelterin subunits Taz1, Rap1 and Poz1 (previously established inhibitors of telomerase) were also found to negatively regulate Ccq1 phosphorylation. These findings establish Tel1ATM/Rad3ATR-dependent Ccq1 Thr93 phosphorylation as a critical regulator of telomere maintenance in fission yeast.