MicroRNA-125b is a novel negative regulator of p53.
The p53 transcription factor is a key tumor suppressor and a central regulator of the stress response. To ensure a robust and precise response to cellular signals, p53 gene expression must be tightly regulated from the transcriptional to the post-translational levels. Computational predictions suggest that several microRNAs are involved in the post-transcriptional regulation of p53. Here we demonstrate that miR-125b, a brain-enriched microRNA, is a bona fide negative regulator of p53 in both zebrafish and humans. miR-125b-mediated down-regulation of p53 is strictly dependent on the binding of miR-125b to a microRNA response element in the 3' untranslated region of p53 mRNA. Overexpression of miR-125b represses the endogenous level of p53 protein and suppresses apoptosis in human neuroblastoma cells and human lung fibroblast cells. In contrast, knockdown of miR-125b elevates the level of p53 protein and induces apoptosis in human lung fibroblasts and in the zebrafish brain. This phenotype can be rescued significantly by either an ablation of endogenous p53 function or ectopic expression of miR-125b in zebrafish. Interestingly, miR-125b is down-regulated when zebrafish embryos are treated with gamma-irradiation or camptothecin, corresponding to the rapid increase in p53 protein in response to DNA damage. Ectopic expression of miR-125b suppresses the increase of p53 and stress-induced apoptosis. Together, our study demonstrates that miR-125b is an important negative regulator of p53 and p53-induced apoptosis during development and during the stress response.
Le
Minh T N
MT
Computation and Systems Biology, Singapore-Massachusetts Institute of Technology Alliance, Singapore.
Teh
Cathleen
C
Shyh-Chang
Ng
N
Xie
Huangming
H
Zhou
Beiyan
B
Korzh
Vladimir
V
Lodish
Harvey F
HF
Lim
Bing
B
D020413:3' Untranslated Regions / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001483:Base Sequence; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004625:Embryo, Nonmammalian / Q000378:metabolism; D005786:Gene Expression Regulation; D018507:Gene Expression Regulation, Developmental; D016158:Genes, p53 / Q000502:physiology*; D005816:Genetic Complementation Test; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D008969:Molecular Sequence Data; D011485:Protein Binding; D013312:Stress, Physiological / Q000502:physiology; D015027:Zebrafish
D020413:3' Untranslated Regions; C531888:MIRN125 microRNA, human; D035683:MicroRNAs