来自德国马克斯-普朗克生物化学研究所(Max-Planck-Institute of Biochemistry)分子肿瘤学的研究人员Heiko Hermeking在本期(2007年11月)Cell子刊Cancer Cell上发表了一篇有关p53与microRNA之间
关系的综述,受到了本领域及相关研究领域的关注。
微小RNA (microRNA,简称miRNA)是生物体内源长度约为20-23个核苷酸的非编码小RNA,通过与靶mRNA的互补配对而在转录后水平上对基因的表达进行负调控,导致mRNA的降解或翻译抑制。对于miRNAs的研究起始于时序调控小RNA(stRNAs),由于miRNAs在物种进化中相当保守,在植物、动物和真菌中发现的miRNAs只在特定的组织和发育阶段表达,而且这种特异性和时序性,决定了组织和细胞的功能特异性,表明miRNA在细胞生长和发育过程的调节过程中起多种作用,因此miRNA的研究受到了生物学家的广泛关注。
近年来,越来越多的研究证实这种小分子RNA——microRNA与高等动植物大量基因的调节有关,并且还与癌症等人类疾病有关。这种分子的研究也是近年来癌症科学领域一个越来越热的研究聚焦点。
去年一项由冷泉港实验室完成的研究中,发现了一个辅助p53途径抑制肿瘤生长的miRNA家族,他们不仅发现p53能够抑制肿瘤生长甚至根除肿瘤,而且发现了一些增强p53途径的怪物质。在那篇文章中,作者认为即便在癌症的最后阶段,之前被破坏的p53途径的再生都能使肿瘤停止生长,甚至通过激活周围健康细胞的免疫反应消除肿瘤。大多数人猜测是蛋白赋予了p53这种能力,但最新研究成果显示是miRNA提高了p53抗肿瘤增生的效果。
而近期,7个研究团体发现了由肿瘤抑制因子p53编码的转录因子调控的miRNAs,这些研究强调出miRNAs:miR-34a和miR-34b/c是直接的,保守的p53的靶标基因,介导了细胞凋亡的诱发,细胞周期的停滞以及衰老。由于这些miRNA也许调控了数以百计的不同蛋白的表达水平,因此这些发现提出了p53网络一个新的,挑战性的复杂平台,综述中也提到有关miR-34基因是p53功能的核心介导因子的证据。
原始出处:
Cancer Cell, Vol 12, 414-418, 13 November 2007
Minireview
p53 Enters the MicroRNA World
Heiko Hermeking1,
1 Molecular Oncology, Max-Planck-Institute of Biochemistry, Am Klopferspitz 18, D-82152 Martinsried, Germany
Corresponding author
Heiko Hermeking
herme@biochem.mpg.de
Recently, microRNAs, which are regulated by the transcription factor encoded by the tumor suppressor gene p53, were identified independently by seven groups. Their studies highlight the microRNAs miR-34a and miR-34b/c as direct, conserved p53 target genes that presumably mediate induction of apoptosis, cell cycle arrest, and senescence by p53. Since these microRNAs may regulate the levels of hundreds of different proteins, these findings add a new, challenging layer of complexity to the p53 network. The initial evidence suggesting that miR-34 genes are central mediators of p53 function is summarized here.
附:
Molecular Oncology (Heiko Hermeking, MPG)
The aim of our group is to understand the function and regulation of the transcription factors p53 and c-MYC, as well as the processes and genes which they regulate. c-MYC and p53 are encoded by genes which are altered in more than 50% of all cancers. The tumor suppressor gene product p53 is activated after DNA damage and induces genes, as 14-3-3sigma, which mediate cell cycle inhibition. We are studying the biology of 14-3-3sigma by structural, proteomic and genetic approaches. p53 is an integral part of a program that mediates cellular senescence and preserves genomic integrity. In contrast, activation of the c-MYC oncogene leads to immortalization and genomic instability. How these effects of oncogenic c-MYC activation are mediated is a focus of our studies. In addition, we are identifying and characterizing genetic and epigenetic alterations which contribute to prostate cancer and malignant melanoma.