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 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.
Tarasov
Valery
V
Molecular Oncology, Max-Planck-Institute of Biochemistry, Am Klopferspitz 18, D-82152 Martinsried, Germany.
Jung
Peter
P
Verdoodt
Berlinda
B
Lodygin
Dmitri
D
Epanchintsev
Alexey
A
Menssen
Antje
A
Meister
Gunter
G
Hermeking
Heiko
H
D017209:Apoptosis / Q000235:genetics*; D001483:Base Sequence; D002874:Chromosome Mapping; D004249:DNA Damage / Q000235:genetics; D016193:G1 Phase / Q000235:genetics*; D005786:Gene Expression Regulation; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000502:physiology*; D008969:Molecular Sequence Data; D017423:Sequence Analysis, RNA; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D016159:Tumor Suppressor Protein p53