Differential Regulation of microRNAs by p53 Revealed by Massively Parallel Sequencing: miR-34a is a p53 Target That Induces Apoptosis and G1-arrest

• Published in: Cell cycle (Georgetown, Tex.) Vol. 6; no. 13; pp. 1586 - 1593
• Main Authors: Tarasov, Valery, Jung, Peter, Verdoodt, Berlinda, Lodygin, Dmitri, Epanchintsev, Alexey, Menssen, Antje, Meister, Gunter, Hermeking, Heiko
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01-07-2007
• Subjects: Apoptosis - genetics; Base Sequence; Binding; Biology; Bioscience; Calcium; Cancer; Cell; Chromosome Mapping; Cycle; DNA Damage - genetics; G1 Phase - genetics; Gene Expression Regulation; Humans; Landes; MicroRNAs - genetics; MicroRNAs - physiology; Molecular Sequence Data; Organogenesis; Proteins; Sequence Analysis, RNA; Tumor Cells, Cultured; Tumor Suppressor Protein p53 - physiology
• ISSN: 1538-4101; 1551-4005
• DOI: 10.4161/cc.6.13.4436

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.