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Cell:RAS二聚体研究取得重大进展

2018-01-15  来源:艾兰博曼医学网  作者:鱼会飞  编辑:陌莉花开
导读
RAS基因突变是癌症最为常见的遗传驱动因素之一,特别是在胰腺癌和肺癌等侵袭性的癌症中,虽然经过了数十年的努力,但是针对RAS突变的癌症患者仍然没有特效的药物。

RAS基因突变是癌症最为常见的遗传驱动因素之一,特别是在胰腺癌和肺癌等侵袭性的癌症中,虽然经过了数十年的努力,但是针对RAS突变的癌症患者仍然没有特效的药物。

西南大学西蒙斯癌症中心的研究人员表明,RAS分子是以二聚体的形式存在的,RAS突变后会导致癌症的发生,这项新的发现可能有助于指导现在患者的治疗。

放射肿瘤学与生物化学副教授Kenneth Westover博士表示,RAS突变是癌症最常见的原因之一,现在没有有效的治疗方法。RAS二聚体的活化为接下来的研究打下了坚实的基础。RAS二聚化的问题已经引起了热烈的讨论,但是研究人员之前还没有证明RAS二聚体具体是什么样,限制了研究人员设计实验的能力,进一步阻止了评估他们在正常生理学和癌症中的重要性。Westover博士领导的UT Southwestern团队使用X射线晶体学数据预测RAS二聚体可能的样子,然后使用荧光共振能量转移(FRET)测试细胞模型中何时为二聚体,何时不是。

这项研究结果发表在《Cell》上,为进一步深入研究RAS生物学提供了基础,并有可能为开发靶向RAS二聚化的新癌症药物铺平了道路。

RAS的主要功能是传递信息,促使细胞的生长和分裂,但是在癌症患者中该信号通路不能正常进行。通过这项新的研究发现,RAS蛋白需要二聚化以高效的传递细胞信号,而且成为RAS突变成为RAS二聚化的关键事件。

Westover研究实验室的成员与Dana Farber癌症研究所的研究人员合作,表明RAS二聚体在许多癌症细胞系统和癌症动物模型中是必不可少的。

英文原文:

Researchers demonstrate RAS dimers are essential for cancer

Mutated RAS genes are some of the most common genetic drivers of cancer, especially in aggressive cancers like pancreatic and lung cancer, but no medicines that target RAS are available despite decades of effort.

Researchers at UT Southwestern's Simmons Cancer Center have shown that RAS molecules act in pairs, known as dimers, to cause cancer, findings that could help guide them to a treatment.

"RAS mutations are one of the most common causes of cancer and there are no options for attacking them. The dimerization activity of RAS gives us a solid lead for moving forward," said Dr. Kenneth Westover, Assistant Professor of Radiation Oncology and Biochemistry with the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern Medical Center, which is recognizing its 75th anniversary this year.

The question of RAS dimerization has been hotly debated, he said, but researchers previously haven't been able to prove what RAS dimers look like, limiting the ability to design experiments that assess their importance in normal physiology and cancer. The UT Southwestern team led by Dr. Westover used X-ray crystallography data to predict what a RAS dimer might look like, then tested the model in cells using a method called fluorescence resonance energy transfer (FRET) to show when RAS forms dimers and when it does not.

The study, published in the journal Cell, provides a foundation for further studies that delve into RAS biology and could potentially pave the way to develop new cancer drugs that target RAS dimerization.

"The primary function of RAS is to transmit signals that tell a cell to grow and divide, a pathway commonly hijacked in cancer. What became clear in our studies is that RAS needs to dimerize to efficiently pass signals in cells. Moreover, RAS dimerization appears to be a crucial event for mutated forms of RAS to cause cancer," said Dr. Westover, part of the Simmons Lung Cancer Team.

Members of the Westover research lab teamed up with researchers from the Dana Farber Cancer Institute to show that RAS dimers are essential in a number of cancer cell systems and animal models of cancer.



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