企业邮箱
世界生命科学前沿动态周报（四十六）
（5.2-5.8/2011）
美宝国际集团:陶国新
主要内容：端粒酶在肿瘤生长中作用的新发现；发现线粒体的新控制机制；突变组织干细胞类似肿瘤干细胞；乳腺癌细胞对雌激素信号的快速广泛而短暂的转录反应；无抗原刺激激活沉寂的T细胞。
1. 端粒酶在肿瘤生长中作用的新发现
【动态】
美国UT Southwestern Medical Center的科学家发现了端粒酶在体内的不同作用模式。端粒酶如何在体内起作用的特定信息对于理解人体肿瘤细胞里端粒的动力学是必须的。该研究的结果提示，在自我平衡的维持端粒长度的条件下，在每次细胞分裂时在每个端粒上只有一个分子的端粒酶起作用顺序在每个末端加上大约60个核苷酸。相反，当端粒延长时（非平衡条件）在每个端粒上有多个分子的端粒酶起作用。长期用端粒酶抑制剂Imetelstat治疗反转后的头几周时间里，Cajal体还不能将端粒酶RNA运送到端粒，这时期端粒酶驱动的延长进行的比较少。这一结果揭示Cajal体对端粒酶的处理可能影响端粒酶的持续合成能力。过表达的端粒酶也比自然表达的端粒酶处理能力差。这些发现显示了体内端粒酶采用的两种不同的主要延长模式。
【点评】
该研究发现在不同条件下端粒酶用不同的模式维持和延长端粒长度。进一步阐明这些模式及其涉及的重要生物靶点，对于更好的理解肿瘤细胞的生命活动以及寻找相应的对策有重要意义。
【参考论文】Molecular Cell, 2011; 42 (3): 297-307 DOI:10.1016/j.molcel.2011.03.020
Processive and Distributive Extension of Human Telomeres by Telomerase under Homeostatic and Nonequilibrium Conditions
Yong Zhao, Eladio Abreu, Jinyong Kim, et al.
Specific information about how telomerase acts in vivo is necessary for understanding telomere dynamics in human tumor cells. Our results imply that, under homeostatic telomere length-maintenance conditions, only one molecule of telomerase acts at each telomere during every cell division and processively adds 60 nt to each end. In contrast, multiple molecules of telomerase act at each telomere when telomeres are elongating (nonequilibrium conditions). Telomerase extension is less processive during the first few weeks following the reversal of long-term treatment with the telomerase inhibitor Imetelstat (GRN163L), a time when Cajal bodies fail to deliver telomerase RNA to telomeres. This result implies that processing of telomerase by Cajal bodies may affect its processivity. Overexpressed telomerase is also less processive than the endogenously expressed telomerase. These findings reveal two major distinct extension modes adopted by telomerase in vivo.
2. 发现线粒体的新控制机制
【动态】
线粒体DNA基因表达的精确控制对于调节哺乳动物的氧化磷酸化能力至关重要。在此过程中MTERF蛋白家族起重要作用，其家族成员涉及了转录起始和位点专一性转录终止的调节。瑞典和德国科学家的一项新研究证明其成员之一，MTERF4，直接控制线粒体核糖体的生源合成和翻译。MTERF4按一定比例与核糖体RNA甲基转移酶NSUN4形成复合物并为大核糖体亚基招募NSUN4所必须。缺少MTERF4导致核糖体组装障碍和蛋白翻译的急剧减少。因此，该研究结果表明MTERF4是哺乳动物线粒体内蛋白翻译的重要调控子。在缺少MTERF4的老鼠中没有形成有功能的核糖体，无法翻译新蛋白，影响线粒体正常功能，使能量生产减少。在数种遗传病以及正常衰老和年龄相关性疾病中都牵涉到线粒体功能减退。
【点评】
线粒体是细胞生命活动的主导，线粒体本身的代谢活动因而对细胞至关重要。对于线粒体代谢活动的任何深入了解都会极大地帮助我们发现维持细胞正常生命活动的条件。
【参考论文】Cell Metabolism, 2011; 13 (5): 527-539 DOI: 10.1016/j.cmet.2011.04.002
MTERF4 Regulates Translation by Targeting the Methyltransferase NSUN4 to the Mammalian Mitochondrial Ribosome
Yolanda Cámara, Jorge Asin-Cayuela, Chan Bae Park, et al.
Precise control of mitochondrial DNA gene expression is critical for regulation of oxidative phosphorylation capacity in mammals. The MTERF protein family plays a key role in this process, and its members have been implicated in regulation of transcription initiation and site-specific transcription termination. We now demonstrate that a member of this family, MTERF4, directly controls mitochondrial ribosomal biogenesis and translation. MTERF4 forms a stoichiometric complex with the ribosomal RNA methyltransferase NSUN4 and is necessary for recruitment of this factor to the large ribosomal subunit. Loss of MTERF4 leads to defective ribosomal assembly and a drastic reduction in translation. Our results thus show that MTERF4 is an important regulator of translation in mammalian mitochondria.
3. 突变组织干细胞类似肿瘤干细胞
【动态】
上皮干细胞自我更新的同时维持多能性，已知缺少蛋白激酶MAP3K4的滋养层干细胞（TS细胞）同时维持了干细胞特性和上皮-间质过渡态特性。美国北卡大学的新研究显示MAP3K4控制了组蛋白乙酰基转移酶CBP的活动，而维持上皮表型需要CBP来乙酰化组蛋白H2A 和 H2B。 MAP3K4/CBP的活性同时缺失抑制了上皮基因的表达导致TS 细胞在维持其自我更新和多能性的同时进行EMT上皮-间质转换。MAP3K4缺陷的TS 细胞的表达谱明确了一种 H2B 乙酰化调节的基因标签，与人体乳腺癌细胞的紧密重叠。总的看来，该研究明确了一种表观遗传开关在TS细胞中维持其上皮表型并且揭示了前所未知的可能对乳腺癌起作用的基因。只改变了正常TS组织干细胞的一个氨基酸，这些突变干细胞在维持自我更新的同时表现出非常类似于预期是肿瘤干细胞特性的高转移性和高侵袭性。
【点评】
肿瘤干细胞和正常组织干细胞共用某些分子信号机制，表观调控决定着细胞命运。正常组织干细胞能够突变成肿瘤干细胞而针对肿瘤干细胞这些分子信号机制的干预也必然影响正常组织干细胞。
【参考论文Cell Stem Cell, Volume 8, Issue 5, 525-537, DOI:10.1016/j.stem.2011.03.008
MAP3K4/CBP-Regulated H2B Acetylation Controls Epithelial-Mesenchymal Transition in Trophoblast Stem Cells
Amy N. Abell, Nicole Vincent Jordan, Weichun Huang, et al.
Epithelial stem cells self-renew while maintaining multipotency, but the dependence of stem cell properties on maintenance of the epithelial phenotype is unclear. We previously showed that trophoblast stem (TS) cells lacking the protein kinase MAP3K4 maintain properties of both stemness and epithelial-mesenchymal transition (EMT). Here, we show that MAP3K4 controls the activity of the histone acetyltransferase CBP, and that acetylation of histones H2A and H2B by CBP is required to maintain the epithelial phenotype. Combined loss of MAP3K4/CBP activity represses expression of epithelial genes and causes TS cells to undergo EMT while maintaining their self-renewal and multipotency properties. The expression profile of MAP3K4-deficient TS cells defines an H2B acetylation-regulated gene signature that closely overlaps with that of human breast cancer cells. Taken together, our data define an epigenetic switch that maintains the epithelial phenotype in TS cells and reveals previously unrecognized genes potentially contributing to breast cancer.
4. 乳腺癌细胞对雌激素信号的快速广泛而短暂的转录反应
【动态】
美国西南医学中心的新研究用GRO-seq方法测定了雌激素信号对乳腺癌细胞转录谱的直接作用。通过新的生物信息学方法分析所得数据使我们能够直接从中鉴别出转录物。发现雌激素信号以快速、强力和出乎预料的短暂方式直接调节很大部分转录谱。除了编码蛋白的基因，雌激素还调节所有三种RNA聚合酶的分布和作用以及几乎每一种迄今发现的非编码RNA。该研究结果最全面的测定了迄今主要的和直接的雌激素作用，提供资源帮助理解其他体系中快速信号依赖的转录活动。雌激素是乳腺癌生长的起始驱动力。
【点评】
雌激素对转录谱的快速广泛的作用表明了非基因因素及表观调控对生命活动的巨大影响。
【参考论文】 Cell, 05 May 2011 DOI: 10.1016/j.cell.2011.03.042
A Rapid, Extensive, and Transient Transcriptional Response to Estrogen Signaling in Breast Cancer Cells
Nasun Hah, Charles G. Danko, Leighton Core, et al.
We report the immediate effects of estrogen signaling on the transcriptome of breast cancer cells using global run-on and sequencing (GRO-seq). The data were analyzed using a new bioinformatic approach that allowed us to identify transcripts directly from the GRO-seq data. We found that estrogen signaling directly regulates a strikingly large fraction of the transcriptome in a rapid, robust, and unexpectedly transient manner. In addition to protein-coding genes, estrogen regulates the distribution and activity of all three RNA polymerases and virtually every class of noncoding RNA that has been described to date. We also identified a large number of previously undetected estrogen-regulated intergenic transcripts, many of which are found proximal to estrogen receptor binding sites. Collectively, our results provide the most comprehensive measurement of the primary and immediate estrogen effects to date and a resource for understanding rapid signal-dependent transcription in other systems.
5. 无抗原刺激激活沉寂的T细胞
【动态】
第一次有直接证据表明蛋白Foxp1主动维持T细胞的沉寂状态直到其被免疫系统的其它部分唤醒。敲除Foxp1蛋白的老鼠T细胞被激活行使其警戒功能。转录因子Foxp1执行必需的天然T细胞沉寂状态的细胞内在调节。美国Wistar研究所报道了缺少转录因子Foxp1的成熟的天然CD8+T细胞获得了效应器表型和功能并且在体外直接响应IL-7 而增殖。Foxp1拮抗Foxo1而抑制IL-7Rα的表达，负向调节激酶MEK和ErK的信号。在淋巴细胞充盈的老鼠中快速删除Foxp1 诱导了天然T细胞获得效应器表型并增殖。Foxp1缺陷的天然CD8+T细胞甚至能够在缺乏主要的I类组织相容性复合物的淋巴细胞减少性老鼠中增殖。该研究证明了淋巴细胞沉寂是通过包括转录调节在内的主动维持机制获得的。
【点评】
该研究证明免疫细胞的待命状态并不是简单的被动默认功能，而是一个涉及到转录因子的主动控制过程。这一发现也说明了生命机制的精密和有秩序，但也为相关干预提供了可能。
【参考论文】Nature Immunology, 2011; DOI: 10.1038/ni.2034
Transcription factor Foxp1 exerts essential cell-intrinsic regulation of the quiescence of naive T cells
Xiaoming Feng, Haikun Wang, Hiroshi Takata, et al.
The molecular mechanisms that underlie T cell quiescence are poorly understood. Here we report that mature naive CD8+ T cells lacking the transcription factor Foxp1 gained effector phenotype and function and proliferated directly in response to interleukin 7 (IL-7) in vitro. Foxp1 repressed expression of the IL-7 receptor α-chain (IL-7Rα) by antagonizing Foxo1 and negatively regulated signaling by the kinases MEK and Erk. Acute deletion of Foxp1 induced naive T cells to gain an effector phenotype and proliferate in lympho-replete mice. Foxp1-deficient naive CD8+ T cells proliferated even in lymphopenic mice deficient in major histocompatibility complex class I. Our results demonstrate that Foxp1 exerts essential cell-intrinsic regulation of naive T cell quiescence, providing direct evidence that lymphocyte quiescence is achieved through actively maintained mechanisms that include transcriptional regulation.