合作研究团队解决癌症细胞突变之谜（附原文） - 干细胞行业新闻干细胞之家



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发表于 2015-5-19 13:54 |只看该作者 |倒序浏览 |打印

本帖最后由细胞海洋于 2015-5-21 08:05 编辑 ; K7 _9 Q7 j9 l

http://www.eurekalert.org/pub_releases/2015-05/uoic-crt051815.php0 l4 r' q' Z  ^; N
Collaborative research team solves cancer-cell mutation mystery
Breakthrough has implications for better targeted cancer treatment protocols

UNIVERSITY OF ILLINOIS COLLEGE OF ENGINEERING

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More than 500,000 people in the United States die each year of cancer-related causes. Now, emerging research has identified the mechanism behind one of the most common mutations that help cancer cells replicate limitlessly.1 v5 l( Q6 B/ B0 b0 h

Approximately 85 percent of cancer cells obtain their limitless replicative potential through the reactivation of a specific protein called telomerase (TERT). Recent cancer research has shown that highly recurrent mutations in the promoter of the TERT gene are the most common genetic mutations in many cancers, including adult glioblastoma and hepatocellular carcinoma.$ g) H6 A( p" J$ I" U

TERT stabilizes chromosomes by elongating the protective element at the end of each chromosome in a cell. Scientists have discovered that cells harboring these mutations aberrantly increase TERT expression, effectively making them immortal.

Now, a collaborative team of researchers at the University of Illinois at Urbana-Champaign and at the University of California, San Francisco, has uncovered the mechanisms by which these common mutations result in elevated TERT expression. The team's findings, published May 14 in Science, have exciting implications for new, more precise and personalized cancer treatments with fewer side effects compared with current treatments.
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By integrating computational and experimental analyses, the researchers identified that the mechanism of increased TERT expression in tumor tissue relies on a specific transcription factor that selectively binds the mutated sequences. A transcription factor is a protein that binds specific DNA sequences and regulates how its target genes are expressed (in this case the gene that expresses TERT). Thus, the TERT mutations act as a new binding site for the transcription factor that controls TERT expression. The newly identified transcription factor does not recognize the normal TERT promoter sequence, and thus, does not regulate TERT in healthy tissue.
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The researchers at Illinois include H. Tomas Rube, Alex Kreig, Sua Myong, and Jun S. Song. UCSF collaborators include Robert J. A. Bell, Andrew Mancini, Shaun F. Fouse, Raman P. Nagarajan, Serah Choi, Chibo Hong, Daniel He, Melike Pekmezci, John K. Wiencke, Margaret R. Wrensch, Susan M. Chang, Kyle M. Walsh, and Joseph F. Costello. The first author, Robert Bell, is a graduate student at UCSF co-mentored by Dr. Song and Dr. Costello.2 D" t0 ^  Y& k1 D1 G

The team's work further showed that the same transcription factor recognizes and binds the mutant TERT promoter in tumor cells from four different cancer types, underscoring that this is a common mechanism of TERT reactivation.0 O+ c0 ^( q* S% I! Y, r' f; [6 g

The identified transcription factor and its regulators have great potential for the development of new precision therapeutic interventions in cancers that harbor the TERT mutations. A treatment that would inhibit TERT in a targeted cancer-cell-specific manner would bypass the toxicities associated with current treatments that inadvertently also target TERT in normal healthy cells.
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Based on these new findings, the team is now conducting a variety of experiments designed to test whether inhibiting the transcription factor activity would not only turn down TERT expression, but might also result in selective cancer cell death.$ ^9 k% B* h3 x& [

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This project was enhanced by the complementary analysis conducted by three research groups located across the country. Joseph F. Costello's laboratory at UCSF is linked to the UCSF Medical Center and the Helen Diller Family Comprehensive Cancer Center, which allowed for access to human tumor samples that generated the cell cultures and produced relevant models. Jun Song's group at Illinois provided advanced computational analysis of the genomic data and predictions that narrowed in on possible mechanisms behind the previously identified mutation. Finally, through single-molecule analysis, Su-A Myong's lab at Illinois provided verification that the proposed mechanism operated in the suggested matter./ M4 a5 x# d) V0 p* d% R% F' I8 [" w

The article abstract, "The transcription factor GABP selectively binds and activates the mutant TERT promoter in cancer," is available online at https://www.sciencemag.org/conte ... e.aab0015.abstract.
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Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.
合作研究团队解决癌症细胞突变之谜
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（这一突破有利于开发更好的靶向癌症治疗方案，来自伊利诺斯工学院大学学报）6 d# r& w4 B7 C; v" k' Z, I4 D

美国每年有超过50万的人死于癌症相关疾病。目前新的研究确定了一个肿瘤细胞通过基因突变获得无限增殖能力的机制。

大约85％的肿瘤细胞通过重新激活端粒酶（TERT）获得无限的增殖能力。最近的癌症研究已经表明，TERT基因的启动子存在高频突变，这也是肿瘤中最常出现突变的位置。这一现象在许多癌症细胞中被发现，包括成人成胶质细胞瘤和肝癌。  O, ]1 u& r- K) L& o/ X

细胞中染色体的稳定是通过TERT在染色体末端延伸端粒长度来实现的。科学家发现获得突变后增加TERT的表达，使细胞获得无限增殖能力。2 J2 M+ N: ]' t0 r6 m
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目前，来自University of Illinois at Urbana-Champaign 和 University of California at San Francisco的研究者合作进行了一项相关的研究，他们发现了导致TERT表达量增加的大量突变的形成机制。该合作小组的研究结果，发表在5月14日出版的science 上。这一发现为低副作用肿瘤药物开发的精确化和个体化提供了新思路。$ x3 @% `( v2 V+ S9 C5 f0 V
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通过实验研究和生物信息学分析，研究人员确定了肿瘤组织中增加TERT表达是依赖于一个特异性转录因子，它可以选择性地结合在突变的序列上。（转录因子是结合在特定DNA序列，从而调节靶基因表达的蛋白质）。因此，这个转录因子结合TERT启动子上的突变位点，控制TERT的表达。这个新鉴定的转录因子不能识别正常TERT的启动子序列，因此，在健康组织中不调控TERT的表达。+ T7 E: w! s/ P# Z9 V$ I* C
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该研究团队的进一步研究发现，这一转录因子在其他四种不同的癌症细胞中也具有相同的功能，即识别并结合在肿瘤细胞中突变的TERT启动子上。这暗示着这一TERT表达调控机制可能是在肿瘤细胞中普遍存在的。3 Z, k% M9 U+ n; l

这一新发现的转录因子及其上游调控机制可以用于开发肿瘤（含有TERT突变的肿瘤）的精确治疗。如果药物只针对肿瘤细胞中的突变TERT而对正常组织细胞没有影响，这是目前大部分肿瘤治疗所不具有的。基于这些新的发现，该小组目前正在进行试验验证抑制转录因子的活性是否可以抑制TERT的表达，同时选择性地杀死癌细胞。4 ]0 \. r0 h# m0 T. M
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2楼原文感谢canjian308 提供