The bmi-1 and myc oncogenes collaborate strongly in murine lymphomagenesis, but the basis for this collaboration was not understood. We recently identified the ink4a-ARF tumor suppressor locus as a critical downstream target of the Polycomb-group transcriptional repressor Bmi-1. Others have shown that part of Myc's ability to induce apoptosis depends on induction of p19arf. Here we demonstrate that down-regulation of ink4a-ARF by Bmi-1 underlies its ability to cooperate with Myc in tumorigenesis. Heterozygosity for bmi-1 inhibits lymphomagenesis in Eµ-myc mice by enhancing c-Myc-induced apoptosis. We observe increased apoptosis in bmi-1 −/− lymphoid organs, which can be rescued by deletion of ink4a-ARF or overexpression of bcl2. Furthermore, Bmi-1 collaborates with Myc in enhancing proliferation and transformation of primary embryo fibroblasts (MEFs) in an ink4a-ARF dependent manner, by prohibiting Myc-mediated induction of p19arf and apoptosis. We observe strong collaboration between the Eµ-myc transgene and heterozygosity for ink4a-ARF, which is accompanied by loss of the wild-type ink4a-ARF allele and formation of highly aggressive B-cell lymphomas. Together, these results reinforce the critical role of Bmi-1 as a dose-dependent regulator of ink4a-ARF, which on its turn acts to prevent tumorigenesis on activation of oncogenes such as c-myc.

MAP kinases phosphorylate specific groups of substrate proteins. Here we show that the amino acid sequence FXFP is an evolutionarily conserved docking site that mediates ERK MAP kinase binding to substrates in multiple protein families. FXFP and the D box, a different docking site, form a modular recognition system, as they can function independently or in combination. FXFP is specific for ERK, whereas the D box mediates binding to ERK and JNK MAP kinase, suggesting that the partially overlapping substrate specificities of ERK and JNK result from recognition of shared and unique docking sites. These findings enabled us to predict new ERK substrates and design peptide inhibitors of ERK that functioned in vitro and in vivo. Mitogen-activated protein (MAP) kinases are components of signaling cascades that regulate normal development and pathological processes such as oncogenesis. MAP kinases were identified during biochemical searches for serine/threonine-specific protein kinases stimulated by growth factors in vertebrate cells (for review, see Sturgill and Wu 1991). MAP kinases were also identified in screens for mutations that affect intercellular signaling in yeast, worms, and flies (for review, see Ferrell 1996). Together, these investigations revealed that MAP kinases function in many cell types, are regulated by a diverse group of extracellular stimuli, and mediate a wide variety of cellular responses. MAP kinases can be divided into subfamilies based on specific conserved residues, particularly a TXY motif in the activation loop (Ferrell 1996). The three best-characterized subfamilies in vertebrates are named extracellular-regulated kinase (ERK), c-Jun amino-terminal kinase (JNK, also called stress-activated protein kinase), and p38. There are probably several additional vertebrate MAP kinase subfamilies, since Saccharomyces cerevisiae contains six different MAP kinases (Madhani and Fink 1998). Here we use the name MAP kinase to refer to all members of the family, and the names ERK, JNK, and p38 to refer to members of those subfamilies.MAP kinases function in modules composed of three protein kinases (for review, see Marshall 1994). MAP kinase kinase kinases, such as Raf-1, phosphorylate and thereby activate MAP kinase kinases, such as MEK (MAP kinase kinase or ERK kinase). MAP kinase kinases are serine/threonine and tyrosine-specific protein kinases that phosphorylate the TXY motif and thereby activate MAP kinases. In general, MAP kinases in different subfamilies are members of separate modules and are regulated by distinct extracellular stimuli (for review, see Whitmarsh and Davis 1996). For example, ERK is activated strongly by receptor tyrosine kinases (RTK) such as the epidermal growth factor receptor, whereas JNK is activated strongly by stress stimuli such as ultraviolet light. Several of the signaling pathways leading from extracellular stimuli to the activation of a MAP kinase module are well defined, whereas others have yet to be characterized in detail. Whereas the upstream signaling events that r...

The laboratory rat (Rattus norvegicus) is an indispensable tool in experimental medicine and drug development, having made inestimable contributions to human health. We report here the genome sequence of the Brown Norway (BN) rat strain. The sequence represents a high-quality 'draft' covering over 90% of the genome. The BN rat sequence is the third complete mammalian genome to be deciphered, and three-way comparisons with the human and mouse genomes resolve details of mammalian evolution. This first comprehensive analysis includes genes and proteins and their relation to human disease, repeated sequences, comparative genome-wide studies of mammalian orthologous chromosomal regions and rearrangement breakpoints, reconstruction of ancestral karyotypes and the events leading to existing species, rates of variation, and lineage-specific and lineage-independent evolutionary events such as expansion of gene families, orthology relations and protein evolution.

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.

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