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A microRNA component of the p53 tumour suppressor network

Abstract

A global decrease in microRNA (miRNA) levels is often observed in human cancers1,2, indicating that small RNAs may have an intrinsic function in tumour suppression. To identify miRNA components of tumour suppressor pathways, we compared miRNA expression profiles of wild-type and p53-deficient cells. Here we describe a family of miRNAs, miR-34a–c, whose expression reflected p53 status. Genes encoding miRNAs in the miR-34 family are direct transcriptional targets of p53, whose induction by DNA damage and oncogenic stress depends on p53 both in vitro and in vivo. Ectopic expression of miR-34 induces cell cycle arrest in both primary and tumour-derived cell lines, which is consistent with the observed ability of miR-34 to downregulate a programme of genes promoting cell cycle progression. The p53 network suppresses tumour formation through the coordinated activation of multiple transcriptional targets, and miR-34 may act in concert with other effectors to inhibit inappropriate cell proliferation.

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Figure 1: Expression of miR-34 is correlated with p53 status in MEFs.
Figure 2: Genes encoding miR-34 are direct targets of p53.
Figure 3: miR-34 family miRNAs mediate growth arrest in a variety of cell types.
Figure 4: miR-34 regulates a programme of cell cycle and DNA damage response genes.

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Acknowledgements

We thank members of the Hannon and Lowe laboratories and the Rosetta Biology group for helpful input; M. Zhang and J. Burchard for bioinformatic analysis; J. Guo, C. Raymond and K. Niemeyer for miRNA quantification; J. Schelter and M. Kibukawa for cell cycle analyses and gene expression profiling; R. Diaz, M. Mehaffey, F. Huynh and the Rosetta Gene Expression Laboratory for technical assistance; and R. Dickins, J. Kurland, M. McCurrach, K. Diggins, A. Chicas, B. Stillman and B. Vogelstein for providing reagents and protocols. L.H. is a Fellow of the Helen Hay Whitney Foundation and is supported by a K99 grant from the NCI. S.W.L. and G.J.H. are supported by a program project grant from the NCI and are investigators of the Howard Hughes Medical Institute. This work was also supported in part by a gift from K. W. Davis.

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Correspondence to Michele A. Cleary or Gregory J. Hannon.

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This file contains Supplementary Figures S1-S8, Supplementary Tables S1-S2, Supplementary Methods and additional references. (PDF 3172 kb)

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He, L., He, X., Lim, L. et al. A microRNA component of the p53 tumour suppressor network. Nature 447, 1130–1134 (2007). https://doi.org/10.1038/nature05939

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