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 sugge...

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Bibliographic Details
Published in:Genes & development 2009-04, Vol.23 (7), p.862-876
Main Authors: Le, Minh T N, Teh, Cathleen, Shyh-Chang, Ng, Xie, Huangming, Zhou, Beiyan, Korzh, Vladimir, Lodish, Harvey F, Lim, Bing
Format: Article
Language:English
Subjects:
3' Untranslated Regions - metabolism
Animals
Apoptosis - physiology
Base Sequence
Cell Line
Cell Line, Tumor
Cells, Cultured
Embryo, Nonmammalian - metabolism
Gene Expression Regulation
Gene Expression Regulation, Developmental
Genes, p53 - physiology
Genetic Complementation Test
Humans
MicroRNAs - metabolism
Molecular Sequence Data
Protein Binding
Research Paper
Stress, Physiological - physiology
Zebrafish
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Summary: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.
ISSN:0890-9369
1549-5477
DOI:10.1101/gad.1767609