斯坦福发现强致癌基因背后的致癌机制

凯博思

    美国斯坦福大学医学院的科研人员一项新研究发现，在超过半数人类癌症中以高水平存在的一种蛋白质通过阻断少数几个参与DNA包装与细胞死亡的基因的表达，从而驱动着细胞的生长。

    这组科研人员发现，这种称为Myc的蛋白质通过一种称为微RNA的微小的调控分子起作用，抑制这些基因的表达。这标志着Myc控制的基因的一个子集首次被发现是这种蛋白质的致癌功能的关键参与者，并且提示了对于Myc依赖型癌症的新的治疗靶标。

    “这是思考微RNA以及染色质包装在癌症中的作用的一种不同的方式，”医学博士、理学博士、肿瘤学与病理学教授DeanFelsher说。“我们非常吃惊地发现一种微RNA的过度表达可能模仿Myc的致癌效应。”

    这组科研人员识别出的这些基因制造蛋白质从而管理细胞通过分裂进行自我更新、进入一种称为衰老的休息状态，或者通过细胞程序化自杀永远退役。这些过程的精细控制对于控制或清除可能危险的肿瘤细胞是必要的。

    为Myc蛋白编码的基因是著名的强致癌基因——致癌基因是用于描述突变或不正常表达的时候会导致癌症的基因的一个术语。它调控着一个细胞的大约1万个基因和微RNA的表达。科学家长久以来知道，让Myc失去活性或者阻断它的表达，能够导致依赖Myc的癌细胞停止生长或死亡，还会导致患Myc依赖型实体癌的小鼠的肿瘤消退。这种依赖现象称为癌基因成瘾。

    微RNA是小型的RNA分子（只有大约22个核苷酸），它和Myc一样，可以调控基因表达。此前的研究已经证明了Myc过度表达导致了称为miR-17-92的一族微RNA的水平增加。

    “多年来人们已经知道Myc调控着微RNA的表达，”Felsher说。“但是不清楚这与Myc的致癌功能的关系是怎样的。”

    Li发现，miR-17-92的表达被锁定在“开”的位置上的Myc依赖型癌细胞——不论是在实验室培养皿中生长的还是作为肿瘤在小鼠体内的——会不断分裂，甚至在Myc表达被阻断后也是如此。这提示Myc通过这个微RNA族起作用，从而施加它的致癌作用。

    Li然后寻找了受到Myc过度表达影响和受到miR-17-92影响的基因的重合部分。这个研究组在这些基因中发现了大约401个基因同时因为Myc和miR-17-92而表达增加或者受到抑制。他们选择把重点放在那些被抑制的基因上，因为这些基因表现出了对微RNA的平均更多的结合部位。他们进一步筛选出了被超过1个miR-17-92结合部位调控的15个基因。

    在这些基因中，有5个引人注目。其中4个基因为已知调控DNA如何紧密地围绕蛋白质包裹起来（形成了称为染色质的复合体）的蛋白质编码。这种包装对于让DNA放进细胞核具有必要性，但是这让调控转录的蛋白质难以访问基因。这4种受到Myc和miR-17-92控制的蛋白质通过调控这个染色质的基因的可访问性从而影响细胞的增殖和衰老。之前从未识别出它们是Myc和miR-17-92的靶标。

    第5个基因为一种称为Bim的蛋白编码，它能诱导细胞程序化死亡，即细胞凋亡。这种细胞自杀路径被身体用于清除受损或者不需要的细胞。此前有人报告说，Bim的表达受到了miR-17-92的影响。

    值得注意的是，所有这些蛋白已知都能影响细胞增殖、进入细胞周期的一种休息状态或者细胞凋亡，这部分是通过允许或禁止访问染色质中的紧密包裹的DNA段起作用的。

    “Myc仍然是基因转录和表达的一个通用放大器，”Felsher说。“但是我们的研究表明癌的状态的维持依赖于一个更专注的机制。”

    最后，Li和他的同事证明了抑制这5个目标基因的表达能有效模仿Myc过度表达，这部分缓解了Myc失去活性的影响。至多30%的培养的Myc依赖型癌细胞在缺乏Myc表达的情况下继续生长（相比之下只有11%的对照细胞继续生长），而小鼠的肿瘤在数周时间里或者没能消退，或者出现了复发。

    “肿瘤学的尚未得到解答的最大的问题之一是致癌基因如何导致癌症，以及你是否能够用另一种基因产品替换一个致癌基因，”Felsher说。“这些实验开始揭示出Myc如何影响细胞的自我更新的决定。这也可能帮助我们瞄准对癌表现型有贡献的Myc过度表达的这些方面。”

yuansoul

@仲夏秋夜云 这个英文原文有么，看中文头痛

LK8275610

yuansoul 发表于 2014-8-13 12:25
@仲夏秋夜云 这个英文原文有么，看中文头痛

，您不是看火星文吗

LK8275610

划时代的发现吗？

幻影

yuansoul 发表于 2014-8-13 12:25
@仲夏秋夜云 这个英文原文有么，看中文头痛

机翻英文。。。还要其他语言么。




Researchers at Stanford University School of Medicine, a new study found that more than half of human cancers with high levels of a protein in the presence of a small number of gene expression by blocking DNA packaging and cell death in several participation, thereby driving the cell growth.
    The researchers found that a protein called Myc regulation by tiny RNA molecules called micro-acts to suppress the expression of these genes. A subset of these marks Myc gene was first found to be controlled by the key players of the oncogenic function of this protein, and Myc-dependent prompted for a new cancer therapeutic targets.
    "This is a role of micro RNA thinking and chromatin packaging in cancer in different ways," MD, Ph.D., professor of oncology and pathology DeanFelsher said. "We are very surprised to find that over-expression of a micro-RNA may mimic the carcinogenic effects of Myc."
    The researchers identified these genes make proteins and thus managed to update itself by splitting cells into a resting state called senescence, or suicide by programmed cell retired forever. Fine control of these processes to control or eliminate potential risk for tumor cells is necessary.
    For Myc protein coding genes are known strong oncogene - oncogene is used to describe mutations or abnormal expression of time will lead to a term of cancer genes. It regulates approximately 10,000 genes and micro-RNA expression in a cell. Scientists have long known that, let Myc inactivation or blocking its expression, can cause cancer cells to stop growing dependence Myc or death, but also lead to cancer risk Myc-dependent regression of solid cancers in mice. This dependence phenomenon called oncogene addiction.
    Micro-RNA is a small RNA molecule (only about 22 nucleotides), which, as Myc, can regulate gene expression. Previous studies have demonstrated the level of Myc overexpression resulted in a family called miR-17-92 micro RNA increases.
    "Over the years it has been known Myc regulates the expression of micro-RNA's," Felsher said. "But it is not clear relationship with Myc oncogenic function is like."
    Li found that the expression of miR-17-92 is locked in the "ON" position on the Myc-dependent cancer cells - whether grown in a laboratory dish or as tumors in mice - will continue to divide , Myc expression is true even after being blocked. This suggests that Myc acts through the micro-RNA family, to exert its carcinogenic effect.
    Li then look for the overlap in part by Myc overexpression of miR-17-92 influence and by the impact of genes. The team found about 401 genes in these genes simultaneously because Myc and miR-17-92 and increased expression or suppressed. They chose to focus on those genes is inhibited because of these genes exhibit an average micro more RNA binding site. They were further screened out more than one binding site miR-17-92 15 control genes.
    Among these genes, there are five compelling. 4 wherein the gene regulation of DNA known how tightly wrapped around the protein (to form a complex called chromatin) encoding the protein. This package DNA into the nucleus has to let necessity, but it makes it difficult to access the regulation of gene transcription of proteins. These four kinds of miR-17-92 by Myc and the control protein chromatin by regulating the accessibility of the gene thereby affecting cell proliferation and senescence. Never before they are identified and miR-17-92 Myc target.
    The first five genes coding for a protein called Bim, it can induce programmed cell death, namely apoptosis. This cell suicide path is used to clear the body of unwanted or damaged cells. Earlier it was reported that the expression of Bim affected by miR-17-92's.
    It is noteworthy that all of these proteins are known could affect cell proliferation, cell cycle into the resting state, or a cell apoptosis, in part by allowing or prohibiting access to the densely packed chromatin DNA segment of functioning.
    "Myc is still a general purpose amplifier gene transcription and expression," Felsher said. "But our research shows that maintaining the status of cancer depends on the mechanism for a more focused."
    Finally, Li and his colleagues demonstrated that inhibition of the expression of these five target genes can effectively mimic Myc overexpression, which partially alleviated the loss of activity of Myc. Up to 30% of the culture of the Myc-dependent cancer Myc expression in the absence of continued growth (compared to only 11% of the control cells continue to grow), while the tumors in mice, or in a few weeks did not subside, or there is a recurrence.
    "One of the biggest unanswered question is how oncology oncogenes cause cancer, and whether you can replace with another gene product of a cancer-causing gene," Felsher said. "These experiments revealed that the decision to start Myc affects cell self-renewal. This may also help us to aim at contributing to the cancer phenotype Myc overexpression of these aspects."