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 splicing-factor oncoprotein SRSF1 (also known as SF2/ASF) is upregulated in breast cancers. We investigated SRSF1’s ability to transform human and mouse mammary epithelial cells in vivo and in vitro. SRSF1-overexpressing COMMA-1D cells formed tumors, following orthotopic transplantation to reconstitute the mammary gland. In 3-D culture, SRSF1-overexpressing MCF-10A cells formed larger acini than control cells, reflecting increased proliferation and delayed apoptosis during acinar morphogenesis. These effects required the first RNA-recognition motif and nuclear functions of SRSF1. SRSF1 overexpression promoted alternative splicing of BIM and BIN1 isoforms that lack pro-apoptotic functions and contribute to the phenotype. Finally, SRSF1 cooperated specifically with MYC to transform mammary epithelial cells, in part by potentiating eIF4E activation, and these cooperating oncogenes are significantly co-expressed in human breast tumors. Thus, SRSF1 can promote breast cancer, and SRSF1 itself or its downstream effectors may be valuable targets for therapeutics development.

Recent studies revealed a surprising regenerative capacity of insulin-producing β cells in mice, suggesting that regenerative therapy for human diabetes could in principle be achieved. Physiologic β cell regeneration under stressed conditions relies on accelerated proliferation of surviving β cells, but the factors that trigger and control this response remain unclear. Using islet transplantation experiments, we show that β cell mass is controlled systemically rather than by local factors such as tissue damage. Chronic changes in β cell glucose metabolism, rather than blood glucose levels per se, are the main positive regulator of basal and compensatory β cell proliferation in vivo. Intracellularly, genetic and pharmacologic manipulations reveal that glucose induces β cell replication via metabolism by glucokinase, the first step of glycolysis, followed by closure of K(ATP) channels and membrane depolarization. Our data provide a molecular mechanism for homeostatic control of β cell mass by metabolic demand.