1. Watson School of Biological Sciences, Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA
2. Program in Genetics, Stony Brook University, Stony Brook, New York 11794, USA
3. Rosetta Inpharmatics, 401 Terry Avenue N., Seattle, Washington 98109, USA
4. Advanced Research & Technology, Applied Biosystems, 850 Lincoln Centre Drive, Foster City, California 94404, USA
5. These authors contributed equally to this work.
6. Present address: Memorial Sloan-Kettering Cancer Center, 415 East 68th Street, New York, New York 10021, USA.

Correspondence to: Michele A. Cleary³Gregory J. Hannon¹ Correspondence and requests for materials should be addressed to M.A.C. (Email: michele_cleary@merck.com) or G.J.H. (Email: hannon@cshl.org).

A global decrease in microRNA (miRNA) levels is often observed in human cancers^{1, 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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