在最新一期《基因與發(fā)育》（Gene and Development）雜志網(wǎng)絡(luò)版上，美國懷特海德研究所和新加坡國立大學(xué)的研究人員發(fā)表報(bào)告稱,，他們發(fā)現(xiàn)了可破壞腫瘤抑制基因p53活性的一小段RNA（即小RNA）,。此項(xiàng)研究結(jié)果將對癌癥診斷和治療產(chǎn)生重要影響,，這一發(fā)現(xiàn)的意義還在于再次突出了小RNA研究與人體醫(yī)學(xué)的許多分支，如癌癥學(xué)和再生醫(yī)學(xué)的相關(guān)性和重要性,。
盡管研究人員之前就曾發(fā)現(xiàn)其他基因和小RNA也能調(diào)控p53基因的活性,，不過這種調(diào)控是間接的，而此次研究人員首次證明了小RNA可直接影響p53基因,。
p53基因具有抑制腫瘤形成的功能,，在超過50%的癌癥腫瘤中，p53基因發(fā)生了故障,。懷特海德研究所的博士后研究員周北巖（音譯）說,，對于p53這樣的重要基因來說，保持其在細(xì)胞內(nèi)的合適水平非常重要,。
此項(xiàng)研究還描述了平衡p53基因表達(dá)的另一個調(diào)控機(jī)制,。該小RNA片段通常會減少某個基因轉(zhuǎn)錄為蛋白質(zhì)的次數(shù)，當(dāng)一個小RNA和一個為特定DNA編碼的信使RNA匹配并結(jié)合時,，就會阻止此信使RNA成為蛋白質(zhì)創(chuàng)建模板,。
為了了解小RNA是否直接影響p53基因，研究人員搜尋了與兩個數(shù)據(jù)庫中已知小RNA相匹配的任何位點(diǎn)的p53基因,。在人類,、斑馬魚和其它許多脊椎動物中，只有小RNA125b具有p53基因的目標(biāo)位點(diǎn),，這表明其在經(jīng)進(jìn)化得以保留的細(xì)胞進(jìn)程中具有足夠的重要性,。
研究人員測試了小RNA125b對表達(dá)p53基因的一些細(xì)胞類型（包括人類神經(jīng)細(xì)胞和肺細(xì)胞）的反應(yīng)。當(dāng)研究人員降低了細(xì)胞內(nèi)小RNA125b的數(shù)量時,，p53基因水平和細(xì)胞凋亡（一種由p53基因觸發(fā)的可編程細(xì)胞死亡）數(shù)量都有所上升,；反之，增加小RNA125b的數(shù)量則會降低p53基因水平和細(xì)胞凋亡數(shù)量,。
為了確認(rèn)小RNA125b在正在發(fā)育階段生物體內(nèi)的類似作用,，研究人員利用斑馬魚胚胎展開了實(shí)驗(yàn),。實(shí)驗(yàn)證明，當(dāng)降低胚胎中的小RNA125b水平時,，細(xì)胞的p53基因水平和凋亡數(shù)均有所上升,。
研究人員表示，將這些數(shù)據(jù)放在一起,，p53基因就成了小RNA125b的一個主要目標(biāo),。大多數(shù)小RNA都有多個目標(biāo)，但在極少數(shù)情況下,，一個小RNA只有一個主要目標(biāo),，小RNA125b就是其中之一。（生物谷Bioon.com）
生物谷推薦原始出處：
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.
