MicroRNA: A new component of the p53 signaling pathway
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Three microRNA (miRNA) molecules have been validated as direct transcriptional targets of the p53 tumor suppressor protein, establishing a novel mechanism of p53-mediated growth arrest in mammalian cells.
The tumor suppressor p53 modulates the expression of target genes that promote growth arrest and apoptosis. As such, it is frequently mutated and inactivated in human cancers. The cyclin-dependent kinase inhibitor p21Waf1/Cip1 is a direct target of p53 and can affect most, but not all, of the anti-proliferative capabilities of p53, implicating additional signaling molecules in the promotion of p53-mediated growth arrest. In Nature, Lin He and colleagues show that p53 directly induces the expression of a cluster of microRNA (miRNA) molecules. In turn, these miRNA molecules repress a number of target genes to promote growth arrest.
miRNAs, which silence expression of target genes through the RNA interference pathway, are commonly downregulated in human cancers. To evaluate the importance of miRNAs in the p53 pathway, the authors compared the miRNA expression profile of wild-type and p53-null mouse embryonic fibroblasts that also expressed a variety of oncogenes. Expression of three miRNAs — miR-34a, miR-34b and miR-34c — positively correlated with p53 status. DNA damage upregulated miR-34 levels in wild-type, but not p53-null cells. Oncogene-mediated activation of endogenous p53 induced miR-34 expression with kinetics comparable to that of p21Waf1/Cip1, suggesting that miR-34 is a direct target of p53. Chromatin immunoprecipitation and luciferase assays confirmed that p53 could bind to and activate transcription of miR-34 genes.
Having validated miR-34 as a direct target of p53, the authors next evaluated the effect of miR-34 expression on downstream target genes. Expression of miR-34 inhibited proliferation by inducing cellular senescence and cell cycle arrest at G1. These phenotypes correlated with reduced gene and protein expression of cyclin E2, cyclin dependent kinase 4 (CDK4) and hepatocyte growth factor receptor (c-MET). Expression of these three genes has previously been found to be modulated by p53 activity. The authors also observed decreased phosphorylation of the retinoblastoma tumor suppressor in cells expressing miR-34, which is consistent with low expression of CDK4 and cyclin E2.
These data highlight an important and novel role for miRNA molecules in promoting p53 signaling activity. Remarkably, miR-34-mediated growth arrest can occur in the absence of p21Waf1/Cip1, suggesting that miRNAs represent a p21-independent pathway for p53-dependent tumor suppression. Finally, a previous study found that miR-34a expression induced growth arrest and apoptosis in neuroblastoma cells by silencing the expression of E2f3. Loss of E2f3 activates p53 expression; thus it will be interesting to determine whether p53 signals through miR-34 to promote growth arrest and apoptosis in neuroblastoma.
Emily J. Chenette Signaling Gateway
Reference
Lin He, Xingyue He, Lee P. Lim, Elisa de Stanchina, Zhenyu Xuan, Yu Liang, Wen Xue, Lars Zender, Jill Magnus, Dana Ridzon, Aimee L. Jackson, Peter S. Linsley, Caifu Chen, Scott W. Lowe, Michele A. Cleary & Gregory J. Hannon. A microRNA component of the p53 tumour suppressor network. Nature447, 1130-1134 (2007) | Article | PubMed |
