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

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 pronounce...

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Bibliographic Details
Published in:Cell cycle (Georgetown, Tex.) Tex.), 2007-07, Vol.6 (13), p.1586-1593
Main Authors: Tarasov, Valery, Jung, Peter, Verdoodt, Berlinda, Lodygin, Dmitri, Epanchintsev, Alexey, Menssen, Antje, Meister, Gunter, Hermeking, Heiko
Format: Article
Language:English
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
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Summary: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.
ISSN:1538-4101
1551-4005
DOI:10.4161/cc.6.13.4436