To date, more than 200 microRNAs have been described in humans; however, the precise functions of these regulatory, non-coding RNAs remains largely obscure. One cluster of microRNAs, the mir-17-92 polycistron, is located in a region of DNA that is amplified in human B-cell lymphomas 1 . Here we compared B-cell lymphoma samples and cell lines to normal tissues, and found that the levels of the primary or mature microRNAs derived from the mir-17-92 locus are often substantially increased in these cancers. Enforced expression of the mir-17-92 cluster acted with c-myc expression to accelerate tumour development in a mouse B-cell lymphoma model. Tumours derived from haematopoietic stem cells expressing a subset of the mir-17-92 cluster and c-myc could be distinguished by an absence of apoptosis that was otherwise prevalent in c-myc-induced lymphomas. Together, these studies indicate that non-coding RNAs, specifically microRNAs, can modulate tumour formation, and implicate the mir-17-92 cluster as a potential human oncogene.MicroRNAs (miRNAs) have emerged relatively recently as a new class of small, non-coding RNAs that regulate gene expression. Nascent primary miRNA transcripts (pri-miRNAs) are processed sequentially by two RNase III enzymes, Drosha and Dicer 2,3 , to yield mature miRNAs, ranging from 18 to 24 nucleotides (nt) in length. miRNAs are incorporated into the RNA interference (RNAi) effector complex, RISC, and target specific messenger RNAs Reprints and permissions information is available at npg.nature.com/reprintsandpermissionsCorrespondence and requests for materials should be addressed to G.J.H. (hannon@cshl.edu) or S.M.H. (hammond@med.unc.edu). * These authors contributed equally to this work.Supplementary Information is linked to the online version of the paper at www.nature.com/nature.Microarray data have been deposited in NCBI-GEO under accession numbers GSM45026-GSM45065 and GSE-2399.The authors declare no competing financial interests. -6 and miR-273 (refs 9, 10). Bantam stimulates cell growth and prevents apoptosis in Drosophila 11 , and miR-181 potentiates B-cell differentiation in mammals 12 . These findings, in combination with computational target predictions, are consistent with miRNAs regulating a broad spectrum of physiological and developmental processes. HHS Public AccessMicroarray-based expression studies have indicated specific alterations in human miRNA expression profiles that correlate with particular tumour phenotypes (J.M.T. and S.M.H., unpublished data). Among those that show altered expression, the mir-17-92 cistron is located at 13q31, a genomic locus that is amplified in cases of diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, primary cutaneous B-cell lymphoma and several other tumour types 1,13 . There are only two annotated genes in the epicentre of this amplicon, c13orf25 and GPC5. Previous studies have shown that c13orf25 is the only one of the two genes for which increased expression correlates with the presence of the amplicon 1 . The...

Alternative splicing modulates the expression of many oncogene and tumor-suppressor isoforms. We have tested whether some alternative splicing factors are involved in cancer. We found that the splicing factor SF2/ASF is upregulated in various human tumors, in part due to amplification of its gene, SFRS1. Moreover, slight overexpression of SF2/ASF is sufficient to transform immortal rodent fibroblasts, which form sarcomas in nude mice. We further show that SF2/ASF controls alternative splicing of the tumor suppressor BIN1 and the kinases MNK2 and S6K1. The resulting BIN1 isoforms lack tumor-suppressor activity; an isoform of MNK2 promotes MAP kinase-independent eIF4E phosphorylation; and an unusual oncogenic isoform of S6K1 recapitulates the transforming activity of SF2/ASF. Knockdown of either SF2/ASF or isoform-2 of S6K1 is sufficient to reverse transformation caused by the overexpression of SF2/ASF in vitro and in vivo. Thus, SF2/ASF can act as an oncoprotein and is a potential target for cancer therapy.For about three-quarters of human genes, individual or partial exons can be included in or excluded from different versions of the mature messenger RNA by alternative splicing 1 . Many alternative splicing factors combinatorially affect this process to determine which mRNA isoforms will serve as the templates for protein synthesis in a given cell type, developmental stage or physiological state 2 .SR proteins are a family of RNA-binding proteins that are essential for splicing. They act at multiple steps of spliceosome assembly and function in both constitutive and regulated splicing. Some heterogeneous nuclear ribonucleoprotein (hnRNP) proteins, which rapidly associate with nascent transcripts, have been implicated in the repression of certain alternative splicing events 2 . hnRNP and SR proteins can have antagonistic effects on the alternative splicing of particular exons in several genes 2 . Both types of factor can bind directly to precursor (pre)-mRNA transcripts, eliciting changes in the alternative splicing of various pre-mRNA substrates in a concentration-dependent manner, both in vitro and in transfection experiments 3,4 . Thus, changes in the expression of these proteins can affect the Reprints and permissions information is available online at

The heterogeneity and instability of human tumors hamper straightforward identification of cancer-causing mutations through genomic approaches alone. Herein we describe a mouse model of liver cancer initiated from progenitor cells harboring defined cancer-predisposing lesions. Genome-wide analyses of tumors in this mouse model and in human hepatocellular carcinomas revealed a recurrent amplification at mouse chromosome 9qA1, the syntenic region of human chromosome 11q22. Gene-expression analyses delineated cIAP1, a known inhibitor of apoptosis, and Yap, a transcription factor, as candidate oncogenes in the amplicon. In the genetic context of their amplification, both cIAP1 and Yap accelerated tumorigenesis and were required to sustain rapid growth of amplicon-containing tumors. Furthermore, cIAP1 and Yap cooperated to promote tumorigenesis. Our results establish a tractable model of liver cancer, identify two oncogenes that cooperate by virtue of their coamplification in the same genomic locus, and suggest an efficient strategy for the annotation of human cancer genes.

An active site, cofactor-containing peptide has been obtained in high yield from bovine serum amine oxidase. Sequencing of this pentapeptide indicates: Leu-Asn-X-Asp-Tyr. Analysis of the peptide by mass spectrometry, ultraviolet-visible spectroscopy, and proton nuclear magnetic resonance leads to the identification of X as 6-hydroxydopa. This result indicates that, contrary to previous proposals, pyrroloquinoline quinone is not the active site cofactor in mammalian copper amine oxidases. Although 6-hydroxydopa has been implicated in neurotoxicity, the data presented suggest that this compound has a functional role at an enzyme active site.

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