生物谷報道：美國密歇根大學(xué)的研究人員發(fā)現(xiàn)，一些人們不甚了解的小RNA能夠幫助主控腫瘤抑制基因行使其功能,。三種mciroRNA基因似乎是保護(hù)性基因p53的關(guān)鍵搭檔,，這些分子的缺失可導(dǎo)致發(fā)生一種常見類型的肺癌。
大量的研究已經(jīng)證實,，p53基因是基因組的守護(hù)神,。P53在不同的細(xì)胞脅迫背景下能夠號令由其他基因構(gòu)成的“軍隊”，使受損DNA得以修復(fù)或促使細(xì)胞在受損嚴(yán)重的情況下走向死亡,。P53的一個關(guān)鍵的網(wǎng)絡(luò)效應(yīng)是避免細(xì)胞發(fā)生癌變,。
現(xiàn)在，密歇根大學(xué)醫(yī)學(xué)院的研究人員給出最確鑿的證據(jù)證實,，p53還調(diào)節(jié)來自所謂垃圾基因王國的一些基 因,。事實上，一個細(xì)胞中97％的遺傳物質(zhì)的功能目前還不完全清楚,。
這項新的研究證實,，在“垃圾”DNA中隱藏著正常細(xì)胞如何制服癌癥或屈服于癌癥的關(guān)鍵信息,。這項研究的結(jié)果刊登在最新一期的Current Biology雜志上。
這項研究的發(fā)現(xiàn)使人們對基因和蛋白質(zhì)表達(dá)在大約50％的攜帶p53基因突變的癌癥中被改變的特定機(jī)理有了新的了解,。接下來,，研究人員將會繼續(xù)挖掘p53發(fā)生缺陷和無法正常行使其功能時的詳細(xì)過程。
密歇根大學(xué)的這項研究是近期來自世界各地的實驗室進(jìn)行的四個證實p53獲得一些microRNA基因支持的研究項目的其中之一,。這些研究有助于人們對microRNA功能的進(jìn)一步了解,。
研究人員早就知道了mRNA的重要性。但是直到現(xiàn)在,，人們對microRNA基因仍然知之甚少,。目前已經(jīng)知道m(xù)iRNA調(diào)節(jié)mRNA的水平以及mRNA制造的蛋白質(zhì)的水平。
這個研究組分析了miRNA34家族的三個基因,。他們證實,，miRNA34基因能與p53合作，然后繼續(xù)確定出該家族的哪個基因進(jìn)行調(diào)節(jié),。他們發(fā)現(xiàn),，miRNA34基因?qū)刂萍?xì)胞增殖和分裂時間的其他基因產(chǎn)生影響。他們還發(fā)現(xiàn)miRNA34基因家族調(diào)節(jié)Bcl-2蛋白的水平,，而Bcl-2蛋白是增強(qiáng)細(xì)胞對誘導(dǎo)死亡的刺激的耐受性的一個關(guān)鍵因子,。
研究人員還進(jìn)一步分析了miRNA34基因表達(dá)在人類肺癌細(xì)胞中是否會受到影響。結(jié)果,，他們發(fā)現(xiàn)兩個miRNA34基因的表達(dá)在大約三分之二的肺癌中缺失,。
腺癌代表了最常見類型的非小細(xì)胞肺癌。當(dāng)miRNA34基因的表達(dá)在肺癌細(xì)胞中被恢復(fù)時,，一些異常的生長特征則受到抑制,。發(fā)現(xiàn)microRNA在腫瘤抑制過程中的作用將對未來癌癥治療具有重要意義。
研究人員同時也提醒說,，microRNA單獨是不可能提供新的癌癥治療或者預(yù)防藥物的,。但是，利用miRNA分子尺寸小的本質(zhì),，或許能夠?qū)⒔?jīng)修飾的,、能模擬miRNA功能的核酸分子傳送到體內(nèi)。如果經(jīng)修飾的核酸能夠在更多的研究中證實其效果,，那么研究人員將可能進(jìn)一步進(jìn)行抗癌癥治療的臨床試驗,。
原始出處:
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
[email protected]
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.
