（11.14-11.20/2011）
恒峰g22国际集团:陶国新 

　　重要内容：发现SHARPIN蛋白是内源性β1整合素激活的抑造剂；癌症结合医治的“全能药”；终止皮肤癌形成的信号；人体多能干细胞代谢的调节机造；会排泄红细胞天生素EPO的血管；肿瘤成长离不开分子伴侣介导的自噬。

　　焦点动态：人体多能干细胞代谢的调节机造。

1. 发现SHARPIN蛋白是内源性β1整合素激活的抑造剂
【动态】
　　有序激活整合素对细胞附着、活动和组织的不变都是至关重要的。蛋白Talin 和 kindlin激活β1整合素，但是抵消激活的抑造机造还不明显。芬兰科学家通过RNAi筛选发现SHARPIN蛋白是β1整合素的重要抑造剂。SHARPIN蛋白在人体癌细胞和重要的白血球中抑造β1整合素的职能。在SHARPIN缺点的老鼠中纤维细胞、白血球和角质细胞阐发出加强了的β1整合素作用，而通过重新表白SHARPIN蛋白可能齐全解除这种加强。SHARPIN蛋白直接结合到整合素α亚基的一个守旧的胞质区，抑造整合素招募激活蛋白Talin 和 kindlin。因而，SHARPIN蛋白抑造了β1整合素从无活性到有活性的关键的构象转变。

【点评】
　　该钻研在已知β1整合素的激活蛋白基础上发现了抑造其激活的蛋白，进一步美满了β1整合素的调控机造，对于钻研人体组织若何维持自身的平衡和不变有重要意思。

【参考论文】
Nature Cell Biology, 2011; 13 (11): 1315 DOI: 10.1038/ncb2340
SHARPIN is an endogenous inhibitor of β1-integrin activation
Juha K. Rantala, Jeroen Pouwels, Teijo Pellinen, et al.
Regulated activation of integrins is critical for cell adhesion, motility and tissue homeostasis. Talin and kindlins activate β1-integrins, but the counteracting inhibiting mechanisms are poorly defined. We identified SHARPIN as an important inactivator of β1-integrins in an RNAi screen. SHARPIN inhibited β1-integrin functions in human cancer cells and primary leukocytes. Fibroblasts, leukocytes and keratinocytes from SHARPIN-deficient mice exhibited increased β1-integrin activity, which was fully rescued by re-expression of SHARPIN. We found that SHARPIN directly binds to a conserved cytoplasmic region of integrin α-subunits and inhibits recruitment of talin and kindlin to the integrin. Therefore, SHARPIN inhibits the critical switching of β1-integrins from inactive to active conformations.

2. 癌症结合医治的“全能药”
【动态】
　　由于每种癌症都是一些处于分歧发展阶段的癌细胞的非均匀混合物，其医治就面对一次同时医治多种分歧的病变细胞。一种可信的法子是成立个别化的基因和蛋白图谱，找出指标癌基因并开出专门针对单个病人的靶向医治药物的组合。但是，个别化医学还存在好多现实问题：1）肿瘤时时演变出抗药的类型；2）医治会极其昂贵；3）好多靶向医治药物还没有开发出来。美国科学家就此提出了已在动物尝试中见效的另一种战术：2-脱氧葡萄糖（2DG）与Bcl-2拮抗剂（如ABT）的结合医治。促凋亡蛋白Bak通常被Mcl-1 和 Bcl-xL抑造。只有从Mcl-1 和 Bcl-xL开释出来后，Bak能力诱导凋亡。2DG通过解离Bak-Mcl-1 复合物可能使大量分化糖的细胞，通常是一些脑细胞和大部门癌细胞，做好筹备。之后，ABT可能结合Bcl-xL，解离Bak-Bcl-xL复合物，解放Bak去诱导细胞凋亡。ABT不能穿过血脑樊篱，只有位于脑部以表大量分化糖的癌细胞可能接触2DG和ABT两种物质。由于ABT在极度靠近凋亡末期的阶段直接触发细胞凋亡，2DG-ABT结合医治合用于所有发展阶段的好多种癌症，副作用很幼。

【点评】
　　该钻研通过两种物质的结合使用分两步特异性的使脑表的癌细胞首先失去葡萄糖能量代谢供给继而触发细胞凋亡，能够合用于分歧阶段的多种癌症，副作用是有时辰会引起淋巴细胞和血幼板削减。

【参考论文】
Cancer Research, 2011; DOI: 10.1158/0008-5472.CAN-11-3091
Finding a Panacea Among Combination Cancer Therapies
R. Yamaguchi, G. Perkins.
Since each cancer is a heterogeneous mix of cancer cells at different stages of development, we are faced with trying to treat many different diseased cells all at once. An authentic approach is to build a genomic and proteomic profile of a patient, identify the target oncogenes and prescribe the combination of targeted drugs tailored for that patient. However, there are many practical problems with this personalized medicine approach: (1) cancers often generate treatment-resistant phenotypes, (2) the treatment could be enormously expensive, and (3) most of the targeted drugs have not been developed yet. We propose a different approach: therapies that combine 2-deoxyglucose (2DG) with Bcl-2 antagonists such as ABT-263/737 (ABT). Pro-apoptotic protein Bak is normally sequestered by Mcl-1 and Bcl-xL. Only when Bak is released from both Mcl-1 and Bcl-xL, can it induce apoptosis. 2DG can prime highly glycolytic cells by dissociating Bak-Mcl-1 complex. Cells primed by 2DG are some brain cells and most cancer cells. ABT can bind to Bcl-xL, dissociating Bak-Bcl-xL complex, freeing Bak and inducing apoptosis. Since ABT cannot cross blood-brain barrier, only cells exposed to both agents are highly glycolytic cancer cells located outside the brain. Because ABT directly triggers apoptosis at the step very near the terminal point of apoptosis, 2DG-ABT combination therapies are applicable to many types of cancer at all stages of development, with little side effect.

3. 终止皮肤癌形成的信号
【动态】
　　鳞状细胞癌（SCC）固然很常见，但是其分子机理仍不了然。澳大利亚、波兰和美国科学家的合作钻研在老鼠中发现了高效的SCC抑造物--发育转录因子Grhl3，并证明以Grhl3为指标的miR-21依赖的原癌基因网络加强了人体的SCC。成体表皮中删除Grhl3会引起一种GRHL3的直接靶标PTEN蛋白表白的失落，导致PI3K/AKT/mTOR信号激活诱导的侵袭性SCC８丛璓ten表白可能齐全终止SCC的形成。人体皮肤和头颈SCC中显著削减的GRHL3和PTEN水平与以此二者为靶标的miR-21水平增长有关联。他们的数据将GRHL3-PTEN轴界说为SCC的关键肿瘤抑造蹊径。
【点评】
　　该钻研发现了抑造鳞状皮肤癌形成的分子机造，对于鳞状皮肤癌的预防和医治有重要价值。

【参考论文】
Cancer Cell, Volume 20, Issue 5, 635-648, 15 November 2011
Targeting of the Tumor Suppressor GRHL3 by a miR-21-Dependent Proto-Oncogenic Network Results in PTEN Loss and Tumorigenesis
Charbel Darido, Smitha R. Georgy, Tomasz Wilanowski,  et al.
Despite its prevalence, the molecular basis of squamous cell carcinoma (SCC) remains poorly understood. Here, we identify the developmental transcription factor Grhl3 as a potent tumor suppressor of SCC in mice, and demonstrate that targeting of Grhl3 by a miR-21-dependent proto-oncogenic network underpins SCC in humans. Deletion of Grhl3 in adult epidermis evokes loss of expression of PTEN, a direct GRHL3 target, resulting in aggressive SCC induced by activation of PI3K/AKT/mTOR signaling. Restoration of Pten expression completely abrogates SCC formation. Reduced levels of GRHL3 and PTEN are evident in human skin, and head and neck SCC, associated with increased expression of miR-21, which targets both tumor suppressors. Our data define the GRHL3-PTEN axis as a critical tumor suppressor pathway in SCC.

4. 人体多能干细胞代谢的调节机造
【动态】
　　重要凭据状态学证据，如果人体多能干细胞（hPSCs）含有未成熟的、不能进行生物能量代谢的线粒体。相反，已分化的成体细胞占有枝状的线粒体网络进行氧化磷酸化作为重要的能量起源。线粒体在hPSCs的生物能学和细胞分化中的作用还不确定。美国科学家的最新钻研批注hPSCs有起作用的呼吸复合物可能最大量的亏损氧气。只管如此，hPSCs的ATP出产重要还是靠糖酵解，F1F0 ATP合成酶亏损ATP来部门维持hPSC线粒体膜电位和细胞活力。解耦联蛋白2（UCP2）通过预防线粒体葡萄糖氧化和推进经由底物分流机造的糖酵解调节hPSC的能量代谢。早期的分化使得hPSC增殖变慢，能量代谢降低，UCP2被抑造，导致糖酵解削减，维持或提高了线粒体葡萄糖氧化。异常的UCP2表白侵扰了这一代谢转换侵害了hPSC分化。总之，hSPCs拥有有职能的线粒体也必要UCP2抑造以进行齐全的分化。

【点评】
　　该钻研批注人体多能干细胞占有可能进行氧化磷酸化的线粒体，但是其重要能量起源是糖酵解，其正常分化必要抑造UCP2的作用，使其能量代谢蹊径从糖酵解向氧化磷酸化转变。

【参考论文】
The EMBO Journal, 2011; DOI: 10.1038/emboj.2011.401
UCP2 regulates energy metabolism and differentiation potential of human pluripotent stem cells
Jin Zhang, Ivan Khvorostov, Jason S Hong, et al. 
It has been assumed, based largely on morphologic evidence, that human pluripotent stem cells (hPSCs) contain underdeveloped, bioenergetically inactive mitochondria. In contrast, differentiated cells harbour a branched mitochondrial network with oxidative phosphorylation as the main energy source. A role for mitochondria in hPSC bioenergetics and in cell differentiation therefore remains uncertain. Here, we show that hPSCs have functional respiratory complexes that are able to consume O2 at maximal capacity. Despite this, ATP generation in hPSCs is mainly by glycolysis and ATP is consumed by the F1F0 ATP synthase to partially maintain hPSC mitochondrial membrane potential and cell viability. Uncoupling protein 2 (UCP2) plays a regulating role in hPSC energy metabolism by preventing mitochondrial glucose oxidation and facilitating glycolysis via a substrate shunting mechanism. With early differentiation, hPSC proliferation slows, energy metabolism decreases, and UCP2 is repressed, resulting in decreased glycolysis and maintained or increased mitochondrial glucose oxidation. Ectopic UCP2 expression perturbs this metabolic transition and impairs hPSC differentiation. Overall, hPSCs contain active mitochondria and require UCP2 repression for full differentiation potential.

5. 会排泄红细胞天生素EPO的血管
【动态】
　　几十年来，自身间接体内基因医治被假定为注射重组蛋白的代替步骤。然而，有效的将先前取自患者的细胞再移植回去挑战很大。美国科学家通过基因工程将特定指令引入了血管组织细胞中，构建了人体血源内皮细胞系形成细胞（ECFCs）在四环素调节系统节造下表白EPO，并在免疫缺点老鼠中创建了皮下血管网络可能系统的开释EPO。这些以ECFCs为内表表的血管网络形成了与老鼠脉管系统的有效吻合，使得重组的EPO能够直接开释到血流中。EPO表白激活后，在正常和血虚老鼠中都诱导了红细胞天生。这一过程可能齐全逆转。该步骤使抱病人从频仍的EPO注射中解放出来，削减医治血虚的医疗用度。

【点评】
　　通过基于内皮细胞系形成细胞的基因输送战术，创建了能够调控的EPO体内表白和直接开释入血流的系统，成为注射重组蛋白的代替步骤。

【参考论文】
Blood, 2011; DOI: 10.1182/blood-2011-08-372946
Induction of erythropoiesis using human vascular networks genetically-engineered for controlled erythropoietin release
R.-Z. Lin, A. Dreyzin, K. Aamodt, et al.
For decades, autologous ex vivo gene therapy has been postulated as a potential alternative to parenteral administration of recombinant proteins. However, achieving effective cellular engraftment of previously retrieved patient cells is challenging. Recently, our ability to engineer vasculature in vivo has allowed for the introduction of instructions into tissues by genetically modifying the vascular cells that build these blood vessels. In the present study, we genetically engineered human blood–derived endothelial colony-forming cells (ECFCs) to express erythropoietin (EPO) under the control of a tetracycline-regulated system, and generated subcutaneous vascular networks capable of systemic EPO release in immunodeficient mice. These ECFC-lined vascular networks formed functional anastomoses with the mouse vasculature, allowing direct delivery of recombinant human EPO into the bloodstream. After activation of EPO expression, erythropoiesis was induced in both normal and anemic mice, a process that was completely reversible. This approach could relieve patients from frequent EPO injections, reducing the medical costs associated with the management of anemia. We propose this ECFC-based gene-delivery strategy as a viable alternative technology when routine administration of recombinant proteins is needed.

6. 肿瘤成长离不开分子伴侣介导的自噬
【动态】
　　细胞自噬对于维持哺乳动物细胞的不变和生物能学极度重要。两种钻研的最明显的自噬机造是大自噬和分子伴侣介导的自噬（CMA）。大自噬的行为变动在癌细胞和实体瘤中已有描述，抑造大自噬会推进肿瘤形成。正常细胞通过上调CMA蹊径来对抑造大自噬作出反映。美国科学家的最新钻研批注在分歧类型的癌细胞中都有CMA上调且与大自噬状态无关，另表在分歧类型和起源的人体肿瘤中CMA组分都有增长。体表癌细胞增殖必要CMA，由于它维持恶变细胞的代谢变动特点。在老鼠中用人肺癌细胞异种移植，这些科学家证了然体内癌细胞对CMA的依赖性。抑造CMA延缓了抑造肿瘤的成长，削减了癌转移的数量，并诱导老鼠中已移植的人肺癌组织的萎缩。类似的处置也削减了两种分歧类型的玄色素瘤细胞系的成长的事实意味着针对该自噬蹊径可能有广谱的抗肿瘤潜力。

【点评】
　　该研就了局批注肿瘤成长离不开分子伴侣介导的细胞自噬，从而为癌症医治提供了新的钻研方向。

【参考论文】
Science Translational Medicine, 2011; 3 (109): 109ra117
Chaperone-Mediated Autophagy Is Required for Tumor Growth
Maria Kon, Roberta Kiffin, Hiroshi Koga, et al.
The cellular process of autophagy (literally “self-eating”) is important for maintaining the homeostasis and bioenergetics of mammalian cells. Two of the best-studied mechanisms of autophagy are macroautophagy and chaperone-mediated autophagy (CMA). Changes in macroautophagy activity have been described in cancer cells and in solid tumors, and inhibition of macroautophagy promotes tumorigenesis. Because normal cells respond to inhibition of macroautophagy by up-regulation of the CMA pathway, we aimed to characterize the CMA status in different cancer cells and to determine the contribution of changes in CMA to tumorigenesis. Here, we show consistent up-regulation of CMA in different types of cancer cells regardless of the status of macroautophagy. We also demonstrate an increase in CMA components in human cancers of different types and origins. CMA is required for cancer cell proliferation in vitro because it contributes to the maintenance of the metabolic alterations characteristic of malignant cells. Using human lung cancer xenografts in mice, we confirmed the CMA dependence of cancer cells in vivo. Inhibition of CMA delays xenograft tumor growth, reduces the number of cancer metastases, and induces regression of existing human lung cancer xenografts in mice. The fact that similar manipulations of CMA also reduce tumor growth of two different melanoma cell lines suggests that targeting this autophagic pathway may have broad antitumorigenic potential.