在最新一期《基因与发育》(Gene and Development)杂志网络版上,美国怀特海德研究所和新加坡国立大学的研究人员发表报告称,他们发现了可破坏肿瘤抑制基因p53活性的一小段RNA(即小RNA)。此项研究结果将对癌症诊断和治疗产生重要影响,这一发现的意义还在于再次突出了小RNA研究与人体医学的许多分支,如癌症学和再生医学的相关性和重要性。
尽管研究人员之前就曾发现其他基因和小RNA也能调控p53基因的活性,不过这种调控是间接的,而此次研究人员首次证明了小RNA可直接影响p53基因。
p53基因具有抑制肿瘤形成的功能,在超过50%的癌症肿瘤中,p53基因发生了故障。怀特海德研究所的博士后研究员周北岩(音译)说,对于p53这样的重要基因来说,保持其在细胞内的合适水平非常重要。
此项研究还描述了平衡p53基因表达的另一个调控机制。该小RNA片段通常会减少某个基因转录为蛋白质的次数,当一个小RNA和一个为特定DNA编码的信使RNA匹配并结合时,就会阻止此信使RNA成为蛋白质创建模板。
为了了解小RNA是否直接影响p53基因,研究人员搜寻了与两个数据库中已知小RNA相匹配的任何位点的p53基因。在人类、斑马鱼和其它许多脊椎动物中,只有小RNA125b具有p53基因的目标位点,这表明其在经进化得以保留的细胞进程中具有足够的重要性。
研究人员测试了小RNA125b对表达p53基因的一些细胞类型(包括人类神经细胞和肺细胞)的反应。当研究人员降低了细胞内小RNA125b的数量时,p53基因水平和细胞凋亡(一种由p53基因触发的可编程细胞死亡)数量都有所上升;反之,增加小RNA125b的数量则会降低p53基因水平和细胞凋亡数量。
为了确认小RNA125b在正在发育阶段生物体内的类似作用,研究人员利用斑马鱼胚胎展开了实验。实验证明,当降低胚胎中的小RNA125b水平时,细胞的p53基因水平和凋亡数均有所上升。
研究人员表示,将这些数据放在一起,p53基因就成了小RNA125b的一个主要目标。大多数小RNA都有多个目标,但在极少数情况下,一个小RNA只有一个主要目标,小RNA125b就是其中之一。(生物谷Bioon.com)
生物谷推荐原始出处:
Gene and Development,doi: 10.1101/gad.1767609,Minh T.N. Le,Bing Lim
MicroRNA-125b is a novel negative regulator of p53
Minh T.N. Le1,2, Cathleen Teh3,7, Ng Shyh-Chang2,7, Huangming Xie1,2,4, Beiyan Zhou4, Vladimir Korzh3, Harvey F. Lodish1,4,5,9 and Bing Lim1,2,6,8
1Computation and Systems Biology, Singapore-Massachusetts Institute of Technology Alliance, Singapore 117576;
2Stem Cell and Developmental Biology, Genome Institute of Singapore, Genome, Singapore 138672;
3Fish Developmental Biology, Institute of Molecular and Cell Biology, Proteos, Singapore 138673;
4Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA;
5Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA;
6CLS 442 Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA
7 These authors contributed equally to this work.
The p53 transcription factor is a key tumor suppressor and a central regulator of the stress response. To ensure a robust and precise response to cellular signals, p53 gene expression must be tightly regulated from the transcriptional to the post-translational levels. Computational predictions suggest that several microRNAs are involved in the post-transcriptional regulation of p53. Here we demonstrate that miR-125b, a brain-enriched microRNA, is a bona fide negative regulator of p53 in both zebrafish and humans. miR-125b-mediated down-regulation of p53 is strictly dependent on the binding of miR-125b to a microRNA response element in the 3′ untranslated region of p53 mRNA. Overexpression of miR-125b represses the endogenous level of p53 protein and suppresses apoptosis in human neuroblastoma cells and human lung fibroblast cells. In contrast, knockdown of miR-125b elevates the level of p53 protein and induces apoptosis in human lung fibroblasts and in the zebrafish brain. This phenotype can be rescued significantly by either an ablation of endogenous p53 function or ectopic expression of miR-125b in zebrafish. Interestingly, miR-125b is down-regulated when zebrafish embryos are treated with γ-irradiation or camptothecin, corresponding to the rapid increase in p53 protein in response to DNA damage. Ectopic expression of miR-125b suppresses the increase of p53 and stress-induced apoptosis. Together, our study demonstrates that miR-125b is an important negative regulator of p53 and p53-induced apoptosis during development and during the stress response.