Authors: Tarasov V; Jung P; Verdoodt B; Lodygin D; Epanchintsev A; Menssen A; Meister G; Hermeking H
Abstract: 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.
Keywords: Apoptosis/*genetics; Base Sequence; Chromosome Mapping; DNA Damage/genetics; G1 Phase/*genetics; *Gene Expression Regulation; Humans; MicroRNAs/*genetics/*physiology; Molecular Sequence Data; Sequence Analysis, RNA; Tumor Cells, Cultured; Tumor Suppressor Protein p53/*physiology|
Journal: Cell cycle (Georgetown, Tex.) Volume: 6 Issue: 13 Pages: 1586-93 Date: June 8, 2007 PMID: 17554199 |
Tarasov V, Jung P, Verdoodt B, Lodygin D, Epanchintsev A, Menssen A, Meister G, Hermeking H (2007) Differential regulation of microRNAs by p53 revealed by massively parallel sequencing: miR-34a is a p53 target that induces apoptosis and G1-arrest. Cell cycle (Georgetown, Tex.) 6: 1586-93.
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