生物谷报道:美国密歇根大学的研究人员发现,一些人们不甚了解的小RNA能够帮助主控肿瘤抑制基因行使其功能。三种mciroRNA基因似乎是保护性基因p53的关键搭档,这些分子的缺失可导致发生一种常见类型的肺癌。
大量的研究已经证实,p53基因是基因组的守护神。P53在不同的细胞胁迫背景下能够号令由其他基因构成的“军队”,使受损DNA得以修复或促使细胞在受损严重的情况下走向死亡。P53的一个关键的网络效应是避免细胞发生癌变。
现在,密歇根大学医学院的研究人员给出最确凿的证据证实,p53还调节来自所谓垃圾基因王国的一些基 因。事实上,一个细胞中97%的遗传物质的功能目前还不完全清楚。
这项新的研究证实,在“垃圾”DNA中隐藏着正常细胞如何制服癌症或屈服于癌症的关键信息。这项研究的结果刊登在最新一期的Current Biology杂志上。
这项研究的发现使人们对基因和蛋白质表达在大约50%的携带p53基因突变的癌症中被改变的特定机理有了新的了解。接下来,研究人员将会继续挖掘p53发生缺陷和无法正常行使其功能时的详细过程。
密歇根大学的这项研究是近期来自世界各地的实验室进行的四个证实p53获得一些microRNA基因支持的研究项目的其中之一。这些研究有助于人们对microRNA功能的进一步了解。
研究人员早就知道了mRNA的重要性。但是直到现在,人们对microRNA基因仍然知之甚少。目前已经知道miRNA调节mRNA的水平以及mRNA制造的蛋白质的水平。
这个研究组分析了miRNA34家族的三个基因。他们证实,miRNA34基因能与p53合作,然后继续确定出该家族的哪个基因进行调节。他们发现,miRNA34基因对控制细胞增殖和分裂时间的其他基因产生影响。他们还发现miRNA34基因家族调节Bcl-2蛋白的水平,而Bcl-2蛋白是增强细胞对诱导死亡的刺激的耐受性的一个关键因子。
研究人员还进一步分析了miRNA34基因表达在人类肺癌细胞中是否会受到影响。结果,他们发现两个miRNA34基因的表达在大约三分之二的肺癌中缺失。
腺癌代表了最常见类型的非小细胞肺癌。当miRNA34基因的表达在肺癌细胞中被恢复时,一些异常的生长特征则受到抑制。发现microRNA在肿瘤抑制过程中的作用将对未来癌症治疗具有重要意义。
研究人员同时也提醒说,microRNA单独是不可能提供新的癌症治疗或者预防药物的。但是,利用miRNA分子尺寸小的本质,或许能够将经修饰的、能模拟miRNA功能的核酸分子传送到体内。如果经修饰的核酸能够在更多的研究中证实其效果,那么研究人员将可能进一步进行抗癌症治疗的临床试验。
原始出处:
Current Biology, Vol 17, 1298-1307, 07 August 2007
Article
p53-Mediated Activation of miRNA34 Candidate Tumor-Suppressor Genes
Guido T. Bommer,1 Isabelle Gerin,2 Ying Feng,1 Andrew J. Kaczorowski,5 Rork Kuick,6 Robert E. Love,1 Yali Zhai,3 Thomas J. Giordano,3,6 Zhaohui S. Qin,7 Bethany B. Moore,1 Ormond A. MacDougald,1,2,6 Kathleen R. Cho,1,3,6 and Eric R. Fearon1,3,4,5,6,
1 Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan 48109-2200
2 Department of Molecular and Integrative Physiology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109-2200
3 Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109-2200
4 Department of Human Genetics, University of Michigan School of Medicine, Ann Arbor, Michigan 48109-2200
5 Cell and Molecular Biology Program and University of Michigan School of Medicine, Ann Arbor, Michigan 48109-2200
6 The Cancer Center, University of Michigan School of Medicine, Ann Arbor, Michigan 48109-2200
7 Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan 48109-2200
Corresponding author
Eric R. Fearon
fearon@umich.edu
Background
In response to varied cell stress signals, the p53 tumor-suppressor protein activates a multitude of genes encoding proteins with functions in cell-cycle control, DNA repair, senescence, and apoptosis. The role of p53 in transcription of other types of RNAs, such as microRNAs (miRNAs) is essentially unknown.
Results
Using gene-expression analyses, reporter gene assays, and chromatin-immunoprecipitation approaches, we present definitive evidence that the abundance of the three-member miRNA34 family is directly regulated by p53 in cell lines and tissues. Using array-based approaches and algorithm predictions, we define genes likely to be directly regulated by miRNA34, with cell-cycle regulatory genes being the most prominent class. In addition, we provide functional evidence, obtained via antisense oligonucleotide transfection and the use of mouse embryonic stem cells with loss of miRNA34a function, that the BCL2 protein is regulated directly by miRNA34. Finally, we demonstrate that the expression of two miRNA34s is dramatically reduced in 6 of 14 (43%) non-small cell lung cancers (NSCLCs) and that the restoration of miRNA34 expression inhibits growth of NSCLC cells.
Conclusions
Taken together, the data suggest the miRNA34s might be key effectors of p53 tumor-suppressor function, and their inactivation might contribute to certain cancers.