Tarasov Valery, Jung Peter, Verdoodt Berlinda, Lodygin Dmitri, Epanchintsev Alexey, Menssen Antje, Meister Gunter, Hermeking Heiko
Molecular Oncology, Max-Planck-Institute of Biochemistry, Am Klopferspitz 18, D-82152 Martinsried, Germany.
Cell Cycle. 2007 Jul 1;6(13):1586-93. doi: 10.4161/cc.6.13.4436. Epub 2007 May 11.
In a genome-wide screen for microRNAs regulated by the transcription factor encoded by the p53 tumor suppressor gene we found that after p53-activation the abundance of thirty-four miRNAs was significantly increased, whereas sixteen miRNAs were suppressed. The induction of miR-34a was most pronounced among all differential regulations. Also expression of the primary miR-34a transcript was induced after p53 activation and by DNA damage in a p53-dependent manner. p53 occupied an evolutionarily conserved binding site proximal to the first non-coding exon of miR-34a. Ectopic miR-34a induced apoptosis and a cell cycle arrest in the G1-phase, thereby suppressing tumor cell proliferation. Other p53-induced miRNAs identified here may also have tumor suppressive potential as they are known to suppress the anti-apoptotic factor Bcl2 (miR-15a/16) and the oncogenes RAS and HMGA2 (let-7a). Our results for the first time directly integrate the regulation of miRNA expression into the transcriptional network regulated by p53. siRNAs corresponding to p53-induced miRNAs may have potential as cancer therapeutic agents as RNA interference based therapies are currently emerging.
在一项针对由p53肿瘤抑制基因编码的转录因子所调控的微小RNA（miRNA）的全基因组筛选中，我们发现p53激活后，34种miRNA的丰度显著增加，而16种miRNA受到抑制。在所有差异调控中，miR-34a的诱导最为明显。此外，p53激活后以及DNA损伤时，初级miR-34a转录本的表达以p53依赖的方式被诱导。p53占据了miR-34a第一个非编码外显子近端的一个进化保守结合位点。异位表达的miR-34a诱导细胞凋亡并使细胞周期停滞在G1期，从而抑制肿瘤细胞增殖。此处鉴定出的其他p53诱导的miRNA也可能具有肿瘤抑制潜力，因为它们已知可抑制抗凋亡因子Bcl2（miR-15a/16）以及癌基因RAS和HMGA2（let-7a）。我们的结果首次将miRNA表达的调控直接整合到由p53调控的转录网络中。由于基于RNA干扰的疗法目前正在兴起，与p53诱导的miRNA对应的小干扰RNA（siRNA）可能具有作为癌症治疗药物的潜力。
