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天下生命科学前沿动态周报（七十一）
（12.19-12.25/2011）
一竞技国际集团:陶国新
主要内容：产前喂食甘露糖阻止新生老鼠的先天糖基化代谢疾��；失去Pten的基质纤维母细胞增进肿瘤生长；基于纳米线的单细胞内视镜；隐花色素辅受体介导节律性抑制糖皮质激素受体；HIF-1α缺失加速表皮老化影响再上皮化生；癌细胞能无限破碎的机理。
焦点动态：基于纳米线的单细胞内视镜。
1. 产前喂食甘露糖阻止新生老鼠的先天糖基化代谢疾病
【动态】
糖基化Ia先天疾病是由编码磷酸甘露糖酶2（PMM2）的基因突变引起的糖代谢杂乱 ，造成多系统的疾病伴有严重的精神运动和智力障碍。德国科学家用一种次形态突变的老鼠模子 ，在交配前和有身期通过饮水饲喂母鼠甘露糖 ，其子女纵然携带上述先天疾病的基因突变 ，也能正常发育 ，战胜了该病对胚胎的危险。该效果突显了胚胎发育中糖基化的须要作用 ，可能会引出治疗该种疾病的新要领。
【点评】
该研究有助于更好的明确这一代谢疾病的分子机理和胚胎发育的要害办法 ，有可能第一次为该疾病找到治疗要领。
【参考论文】
Nature Medicine, 2011; DOI:10.1038/nm.2548
Successful prenatal mannose treatment for congenital disorder of glycosylation-Ia in mice
Anette Schneider, Christian Thiel, Jan Rindermann, et al.
Congenital disorder of glycosylation-Ia (CDG-Ia, also known as PMM2-CDG) is caused by mutations in the gene that encodes phosphomannomutase 2 (PMM2, EC 5.4.2.8) leading to a multisystemic disease with severe psychomotor and mental retardation. In a hypomorphic Pmm2 mouse model, we were able to overcome embryonic lethality by feeding mannose to pregnant dams. The results underline the essential role of glycosylation in embryonic development and may open new treatment options for this disease.
2. 失去Pten的基质纤维母细胞增进肿瘤生长
【动态】
基质纤维母细胞的PTEN（磷酸酶）表达抑制了乳腺上皮癌的生长 ，但机理未明。使用卵白质组学和表达图谱测定 ，美国科学家显示乳腺基质纤维母细胞缺失Pten基因会激活致癌的渗透卵白组协调微情形中其他类型细胞的转录重编程。下调miR-320和上调其一个直接靶点ETS2是Pten缺失的基质纤维母细胞诱导致癌的渗透卵白组的要害事务 ，致癌的渗透卵白组转而增进肿瘤爆发和肿瘤细胞侵袭。他们发明肿瘤微情形的纤维母细胞因缺失Pten而导致miR-320数目剧降 ，进而使ETS2卵白数目大涨 ，最终大宗的ETS2卵白激活许多基因 ，使纤维母细胞渗透50多种因子刺激邻近癌细胞的增殖和侵袭 ，也引起肿瘤中和整个乳腺里的其他纤维母细胞重编程。Pten–miR-320–Ets2调理的渗透卵白组的表达区脱离了人体正常的乳腺基质组织与肿瘤基质 ，并与乳腺癌的复发强烈相关。该研究批注miR-320是在基质纤维母细胞中重组肿瘤微情形并阻碍肿瘤生长的Pten肿瘤抑制轴的一个要害部分。
【点评】
该研究增进了关于肿瘤微情形在肿瘤生长中的作用的明确 ，并为防治癌症提供了新的研究途径。
【参考论文】
Nature Cell Biology, 2011; DOI: 10.1038/ncb2396
Reprogramming of the tumour microenvironment by stromal PTEN-regulated miR-320
Bronisz, J. Godlewski, J. A. Wallace, et al.
PTEN (Phosphatase and tensin homolog deleted on chromosome 10) expression in stromal fibroblasts suppresses epithelial mammary tumours, but the underlying molecular mechanisms remain unknown. Using proteomic and expression profiling, we show that Pten loss from mammary stromal fibroblasts activates an oncogenic secretome that orchestrates the transcriptional reprogramming of other cell types in the microenvironment. Downregulation of miR-320 and upregulation of one of its direct targets, ETS2 (v-ets erythroblastosis virus E26 oncogene homolog 2) are critical events inPten-deleted stromal fibroblasts responsible for inducing this oncogenic secretome, which in turn promotes tumour angiogenesis and tumour-cell invasion. Expression of the Pten–miR-320–Ets2-regulated secretome distinguished human normal breast stroma from tumour stroma and robustly correlated with recurrence in breast cancer patients. This work reveals miR-320 as a critical component of the Pten tumour-suppressor axis that acts in stromal fibroblasts to reprogramme the tumour microenvironment and curtail tumour progression.
3. 基于纳米线的单细胞内视镜
【动态】
基于纳米线和纳米管的能够清静穿透细胞膜进入细胞的迅速一维探针在高区分率高通量的基因及药物递送 ，生物感测和单细胞电心理学中有潜在用途。可是 ，这些探针在次波长水平跨膜的光通讯中的使用还受到限制。美国科学家的最新研究显示在光纤锥形尖上贴附一个纳米线波导管能够将可见光引入活的哺乳动物细胞内的区域 ，也能够检测来自亚细胞区域的光信号并有高空间区分率。并且 ，将内视镜插入细胞内及指导激光的光照没有在细胞内引起显着毒性。
【点评】
该手艺的泛起使得直接肉眼视察单个活细胞内亚细胞水平的结构和生运气动成为可能。
【参考论文】
Nature Nanotechnology, 2011; DOI: 10.1038/nnano.2011.226
Nanowire-based single-cell endoscopy
Ruoxue Yan, Ji-Ho Park, Yeonho Choi, et al.
One-dimensional smart probes based on nanowires and nanotubes that can safely penetrate the plasma membrane and enter biological cells are potentially useful in high-resolution, and high-throughput, gene and drug delivery, biosensing, and single-cell electrophysiology. However, using such probes for optical communication across the cellular membrane at the subwavelength level remains limited. Here, we show that a nanowire waveguide attached to the tapered tip of an optical fibre can guide visible light into intracellular compartments of a living mammalian cell, and can also detect optical signals from subcellular regions with high spatial resolution. Furthermore, we show that through light-activated mechanisms the endoscope can deliver payloads into cells with spatial and temporal specificity. Moreover, insertion of the endoscope into cells and illumination of the guided laser did not induce any significant toxicity in the cells.
4. 隐花色素辅受体介导节律性抑制糖皮质激素受体
【动态】
哺乳动物的代谢有高度的节律性 ，涉及核激素受体的主要激素回路体现出互通的昼夜循环。然而 ，合乎逻辑的诠释核激素受体与生物钟之协调的机理还不清晰。美国德国和荷兰的科学家的最新研究显示两个心理节奏的辅受体隐花色素1和2能够以配体依赖的方法与糖皮质激素受体相互作用 ，并在老鼠胚胎纤维母细胞中整体改变对糖皮质激素的转录反应：隐花色素缺失极大地镌汰了基因抑制 ，约莫使地塞米松诱导的基因数目翻倍 ，提醒隐花色素普遍的拮抗糖皮质激素受体激活并增进其抑制。在老鼠中 ，基因缺失隐花色素1和/或2会导致葡萄糖耐受和血循环中结构性的高水平的皮质酮 ，提醒相耦联的肾上腺轴抑制的镌汰和糖皮质激素在肝脏中转活化的增添。从基因上说 ，隐花色素1和2 以激素依赖的方法与磷酸烯醇丙酮酸羧激酶1增进子中糖皮质激素反应因素相关联 ，并且地塞米松诱导的磷酸烯醇丙酮酸羧激酶1基因的转录在缺失隐花色素的肝脏中显著增添。这些效果批注保存一种特殊机制 ，借此隐花色素将生物钟运动和受体靶基因与支持正常代谢平衡的重大基因回路相藕联。
【点评】
该研究发明了身体生物钟和糖代谢系统之间缺失的环节 ，可能有助于诠释睡眠和营养代谢之间的关联。
【参考论文】
Nature. 2011, 480(7378):552-6. doi:10.1038/nature10700.
Cryptochromes mediate rhythmic repression of the glucocorticoid receptor
Katja A. Lamia, Stephanie J. Papp, Ruth T. Yu, et al.
Mammalian metabolism is highly circadian and major hormonal circuits involving nuclear hormone receptors display interlinked diurnal cycling. However, mechanisms that logically explain the coordination of nuclear hormone receptors and the clock are poorly understood. Here we show that two circadian co-regulators, cryptochromes 1 and 2, interact with the glucocorticoid receptor in a ligand-dependent fashion and globally alter the transcriptional response to glucocorticoids in mouse embryonic fibroblasts: cryptochrome deficiency vastly decreases gene repression and approximately doubles the number of dexamethasone-induced genes, suggesting that cryptochromes broadly oppose glucocorticoid receptor activation and promote repression. In mice, genetic loss of cryptochrome 1 and/or 2 results in glucose intolerance and constitutively high levels of circulating corticosterone, suggesting reduced suppression of the hypothalamic-pituitary-adrenal axis coupled with increased glucocorticoid transactivation in the liver. Genomically, cryptochromes 1 and 2 associate with a glucocorticoid response element in the phosphoenolpyruvate carboxykinase 1 promoter in a hormone-dependent manner, and dexamethasone-induced transcription of the phosphoenolpyruvate carboxykinase 1 gene was strikingly increased in cryptochrome-deficient livers. These results reveal a specific mechanism through whichcryptochromes couple the activity of clock and receptor target genes to complex genomic circuits underpinning normal metabolic homeostasis.
5. HIF-1α缺失加速表皮老化影响再上皮化生
【动态】
在老鼠和人体的皮肤中 ，缺氧诱导因子HIF-1α是在表皮 ，主要是基底层中表达。HIF-1α已被证实有主要的系统性功效：在去除表皮中HIF-1α的老鼠中调理肾脏红细胞天生素的生产 ，以及表皮中HIF-1α高表达带来的血管型。可是 ，HIF-1α 在角化细胞心理中的局部作用还没有剖析。法国科学家用敲除靶向角化细胞的HIF-1α基因的老鼠模子来研究HIF-1α在表皮中的作用。这些老鼠皮肤延迟泛起皮肤表型 ，并体现为皮肤萎缩和瘙痒发炎 ，部分缘故原由是牵涉层粘连卵白332（Ln-332）和整合素的基底膜失调。研究者门也用重修的表皮研究了老鼠实验效果与人体皮肤的相关性 ，效果显示在人体角化细胞中抑制HIF-1α基因故障了形成能存活的重修人体表皮。随着HIF-1α静默而降低的角化细胞生长潜力与Ln-322 、 α6 和β1整合素表达 的降低有关。总的说来 ，这些效果批注HIF-1α在皮肤稳态特殊是表皮老化时代饰演一定的角色。
【点评】
该研究展现了HIF-1α在表皮形成中的作用 ，有助于进一步相识皮肤的发育和心理。
【参考论文】
J Cell Sci, 2011, doi:10.1242/jcs.082370
Loss of epidermal hypoxia-inducible factor-1α accelerates epidermal aging and affects re-epithelialization in human and mouse
Hamid Reza Rezvani, Nsrein Ali, Martin Serrano-Sanchez, et al.
In mouse and human skin, HIF-1α is constitutively expressed in the epidermis, mainly in the basal layer. HIF-1α has been shown to have crucial systemic functions: regulation of kidney erythropoietin production in mice with constitutive HIF-1α epidermal deletion, and hypervascularity following epidermal HIF-1α overexpression. However, its local role in keratinocyte physiology has not been clearly defined. To address the function of HIF-1α in the epidermis, we used the mouse model of HIF-1α knockout targeted to keratinocytes (K14-Cre/Hif1aflox/flox). These mice had a delayed skin phenotype characterized by skin atrophy and pruritic inflammation, partly mediated by basement membrane disturbances involving laminin-332 (Ln-332) and integrins. We also investigated the relevance of results of studies in mice to human skin using reconstructed epidermis and showed that HIF-1α knockdown in human keratinocytes impairs the formation of a viable reconstructed epidermis. A diminution of keratinocyte growth potential, following HIF-1α silencing, was associated with a decreased expression of Ln-322 and α6 integrin and β1 integrin. Overall, these results indicate a role of HIF-1α in skin homeostasis especially during epidermal aging.
6. 癌细胞能无限破碎的机理
【动态】
德国、瑞典和瑞士的科学家最近发明了癌细胞能无限破碎的机理 ，这将有助于靶向癌症治疗。就细胞破碎而言 ，恶性肿瘤细胞突破了险些所有纪律。这种细胞在没有外部信号时 ，仍能破碎 ，这些细胞通过旁路而获得关于生长的外部信号 ，以是仍能增殖。关于癌细胞能无限破碎的机制 ，至今科学家们还不是很清晰。该研究的研究职员发明了两个要害因子的作用 ，就是c-Myc和SIRT1 ，在癌细胞中 ，前者能挣脱细胞内的控制机制 ，促使癌细胞破碎。他们发明高度群集的c-Myc卵白可激活一种抑制细胞朽迈和殒命的酶SIRT1 ，而这种酶又可反作用于c-Myc卵白 ，云云形成一个回路 ，令c-Myc卵白和SIRT1酶越来越多 ，最终促使癌细胞无限破碎。之前的研究批注SIRT1卵白在长寿 ，糖代谢 ，以及胰岛素渗透历程中饰演了主要角色。
【点评】
该研究展现延伸细胞寿命与癌细胞生长之间的关联 ，也提出了一种治疗癌症的新靶标系统 ，未来有助于开发新型治疗要领。
【参考论文】
PNAS 2011, doi:10.1073/pnas.1105304109
The c-MYC oncoprotein, the NAMPT enzyme, the SIRT1-inhibitor DBC1, and the SIRT1 deacetylase form a positive feedback loop
Antje Menssen, Per Hydbring, Karsten Kapelle, et al.
Silent information regulator 1 (SIRT1) represents an NAD+-dependent deacetylase that inhibits proapoptotic factors including p53. Here we determined whether SIRT1 is downstream of the prototypic c-MYC oncogene, which is activated in the majority of tumors. Elevated expression of c-MYC in human colorectal cancer correlated with increased SIRT1 protein levels. Activation of a conditional c-MYC allele induced increased levels of SIRT1 protein, NAD+, and nicotinamide-phosphoribosyltransferase (NAMPT) mRNA in several cell types. This increase in SIRT1 required the induction of the NAMPT gene by c-MYC. NAMPT is the rate-limiting enzyme of the NAD+ salvage pathway and enhances SIRT1 activity by increasing the amount of NAD+. c-MYC also contributed to SIRT1 activation by sequestering the SIRT1 inhibitor deleted in breast cancer 1 (DBC1) from the SIRT1 protein. In primary human fibroblasts previously immortalized by introduction of c-MYC, down-regulation of SIRT1 induced senescence and apoptosis. In various cell lines inactivation of SIRT1 by RNA interference, chemical inhibitors, or ectopic DBC1 enhanced c-MYC-induced apoptosis. Furthermore, SIRT1 directly bound to and deacetylated c-MYC. Enforced SIRT1 expression increased and depletion/inhibition of SIRT1 reduced c-MYC stability. Depletion/inhibition of SIRT1 correlated with reduced lysine 63-linked polyubiquitination of c-Myc, which presumably destabilizes c-MYC by supporting degradative lysine 48-linked polyubiquitination. Moreover, SIRT1 enhanced the transcriptional activity of c-MYC. Taken together, these results show that c-MYC activates SIRT1, which in turn promotes c-MYC function. Furthermore, SIRT1 suppressed cellular senescence in cells with deregulated c-MYC expression and also inhibited c-MYC–induced apoptosis. Constitutive activation of this positive feedback loop may contribute to the development and maintenance of tumors in the context of deregulated c-MYC.