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In brief: September 2007Ageing Quantitative mass spectrometry identifies insulin signaling targets in C. elegans. The homologue of the insulin-like growth factor receptor in Caenorhabditis elegans, DAF-2, negatively regulates DAF-16, a class O forkhead box transcription factor, and daf-2 mutants exhibit extended lifespan. John Yates and colleagues used quantitative mass spectrometry (qMS) to identify proteins that are involved in this anti-ageing signalling network. By labelling proteins in daf-2 mutants with 15N and comparing the levels with those in wild-type worms (labelled with 14N) by qMS, they identified 86 proteins that could be important. Several of these were validated using RNA interference, identifying key pathways that confer and limit longevity in daf-2 mutants. Although only 10% of the worm proteome was analysed because of technical limitations, this approach could significantly improve our understanding of signalling networks, including those associated with longevity. Cell adhesion P-selectin primes leukocyte integrin activation during inflammation. The selectin family of cell-adhesion molecules mediate the tethering of leukocytes to activate integrin-mediated leukocyte adhesion in injured tissues, which is vital for the inflammatory response. The signalling pathway by which selectin-mediated tethering occurs has been unknown. Wang et al. now show that P-selectin is needed for leukocyte adhesion, resulting in leukocyte accumulation at sites of inflammation. Binding of P-selectin to the P-selectin glycoprotein ligand-1 (PSGL-1) activates Src kinases, which in turn phosphorylate NEF-associated factor-1 (NAF1). NAF1 recruits the heterodimeric phosphatidylinositol 3-kinase p85–p110 Telomeres Protection of telomeres through independent control of ATM and ATR by TRF2 and POT1. The shelterin complex protects telomeres against DNA-damage-response mechanisms. By depleting either or both of the shelterin proteins TRF2 and POT1 from cells that lack ataxia-telangiectasia mutated (ATM) and/or ataxia-telangiectasia and Rad3-related (ATR) kinase, Denchi and de Lange found that TRF2 and POT1 repress the ATM and ATR DNA-damage-response pathways, respectively. In addition, the fusion of dysfunctional telomeres by non-homologous end joining required either ATM or ATR signalling. T cells Critical regulation of CD4+ T cell survival and autoimmunity by Tight regulation of the numbers and activity of effector T cells is crucial to protect us from developing autoimmune conditions. Here, Shi et al. show that B cells Decreased expression of Krüppel-like factors in memory B cells induces the rapid response typical of secondary antibody responses. Good and Tangye investigated the poorly defined mechanisms that regulate B-cell memory and the rapid recall response to specific antigen rechallenge by comparing the responses of human splenic naive and memory B-cell subsets to defined stimuli in vitro. Gene-expression profiling showed downregulated expression of the cell-cycle regulatory genes Krüppel-like factor 4 (KLF4), KLF9 and promyelocytic leukaemia zinc finger (PLZF) in memory B cells compared with naive B cells. Enforced expression of these genes in memory B cells delayed their entry into division and reduced their proliferation. So, memory B cells seem to have a considerably reduced activation threshold compared with naive B cells that allows them to enter division more rapidly and produce a more robust antibody response. Autoimmunity BAFF and MyD88 signals promote a lupuslike disease independent of T cells. Transgenic mice that overexpress the cytokine B-cell-activating factor (BAFF) develop an autoimmune disease similar to systemic lupus erythematosus (SLE) and have impaired B-cell tolerance and altered differentiation of T cells. Here, the role of T cells in BAFF-driven autoimmune disease was investigated. Baff-transgenic mice that lacked T cells developed a disease indistinguishable from that of Baff-transgenic mice. BAFF also promoted Toll-like receptor 7 (TLR7) and TLR9 expression on and TLR-induced autoantibody production by B cells. Moreover, the induction of disease in Baff-transgenic mice required B-cell-intrinsic signals through the TLR signalling adaptor protein MyD88 (myeloid differentiation primary-response gene 88). The development of BAFF-induced SLE-like disease in Baff-transgenic mice, therefore, is T-cell independent, but B-cell activation and pathogenic autoantibody production requires MyD88-dependent signalling. MicroRNA p53-mediated activation of miRNA34 candidate tumour-suppressor genes Bommer et al. found that p53 can directly regulate transcription of the miR-34 family of microRNAs (miRNAs) in cell lines and mice. Transcriptional arrays on colon cancer cell lines showed that these miRNAs primarily downregulate cell-cycle-associated genes. Although miR-34s induced cell-cycle arrest, they also decreased the levels of the anti-apoptotic protein BCL2, and therefore seem to mediate two key p53 functions. The expression of two miR-34s was significantly reduced in 6 of 14 non-small-cell lung cancer (NSCLC) samples, and ectopic expression of miR-34 in NSCLC cell lines inhibited their growth. Prostate cancer A secreted isoform of ERBB3 promotes osteonectin expression in bone and enhances the invasiveness of prostate cancer cells Prostate cancer preferentially metastasizes to bone. Previously, a secreted isoform of ERBB3 (p45-sERBB3) was detected in metastatic prostate cancer cells isolated from patients and was shown to interact with osteoblasts. Chen et al. now show that p45-sERBB3 stimulates mouse bone to secrete factors including osteonectin, which increases the invasiveness of prostate cancer cells in vitro. Invasion induced by p45-sERBB3 was also blocked by osteonectin antibodies. Thus, p45-sERBB3 and osteonectin might mediate the interactions between metastasizing prostate cancer cells and bone. Oncogenes Wild-type NRAS and KRAS perform distinct functions during transformation Why do cells express two or more wild-type Ras isoforms? Fotiadou et al. used a genetically-defined system of mouse embryo fibroblasts to show that both wild-type KRAS and NRAS are essential for transformation. This is because they have distinct functions: KRAS coordinates motility by signalling through Akt and CDC42, whereas NRAS regulates adhesion by signalling through Raf and RHOA. Microbial genetics A comprehensive genetic characterization of bacterial motility. The authors describe a powerful genome-wide approach to identify the genetic bases of complex bacterial phenotypes. They used libraries of transposon-mutagenized cells, enriched them for cells with abnormal phenotypes by competitive selection, and analysed the genetic determinants of the phenotypes by microarray-based genetic footprinting. Analysis of Escherichia coli motility through this method revealed more than 95% of the previously known flagellar and chemotaxis genes and more than 30 new genes, some of which had not been characterized before. The authors also show the feasibility of this approach for studying gene-by-gene and gene-by-environment interactions. Gene regulation MTERF3 is a negative regulator of mammalian mtDNA transcription. Although components of the basal mitochondrial transcription machinery have been defined at the molecular level, the members that fine-tune levels of mitochondrial transcription to modulate oxidative phosphorylation capacity are poorly understood. The authors show that mitochondrial transcription termination factor 3 (MTERF3) functions as a transcriptional repressor — the first example of a mitochondrial protein that acts as a specific repressor of mammalian mitochondrial DNA transcription initiation in vivo. The gene is essential — knocking it out in mice is embryonic lethal. Moreover, heart-specific MTERF3 inactivation results in increased transcription initiation and, ultimately, severe respiratory-chain deficiency. Addiction Varenicline, an Varenicline, a partial agonist at Development Fibroblast growth factor receptors cooperate to regulate neural progenitor properties in the developing midbrain and hindbrain Midbrain and hindbrain development is regulated in part by the secretion of signalling molecules, including fibroblast growth factors (FGFs), from the isthmic organizer. To understand how the surrounding tissue responds to these signals, the authors generated mice that carried combinations of FGF receptor 1 (Fgfr1), Fgfr2 and Fgfr3 mutations. They show that the actions of the three receptors in regulating cell survival and patterning are partly redundant. Furthermore, in the ventral midbrain, FGFRs regulate dopamine neuron production and have a role in controlling progenitor self-renewal and differentiation. Inflammatory disorders Crucial role of the protein C pathway in governing microvascular inflammation in inflammatory bowel disease. Activated protein C (PC) is a potent anticoagulant and anti-inflammatory molecule. Scaldaferri and colleagues showed that in human inflammatory bowel disease (IBD) there was loss of expression of endothelial PC receptor and thrombomodulin, which in turn caused an impairment of PC activation by the inflamed mucosal microvasculature. In isolated human intestinal endothelial cells, administration of recombinant activated PC had a potent anti-inflammatory effect and in vivo, activated PC ameliorated experimental colitis. These results suggest that restoring the PC pathway may represent a new approach to suppress intestinal inflammation in IBD. RNA interference MicroRNA matchmaking. Computational microRNA target prediction programs usually yield a large number of targets for each microRNA, and deciding which to choose for validation is difficult. Grimson et al. describe five new features that determine the pairing of a microRNA to its target. These features are incorporated into their target-discovery algorithm, TargetScan, and will provide a more stringent selection for microRNA-target pairs. Genomics Mapping an abundance of SNPs. By resequencing the genomes of 15 different laboratory mouse strains, including 11 classical and 4 wild-derived ones, Frazer et al. identified more than 8 million unique single-nucleotide polymorphisms (SNPs) across the mouse genome with oligonucleotide arrays. They used the data to generate an ancestral haplotype map, available online (http://mouse.perlegen.com). | |
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complex and this leads to integrin activation. Elucidation of the PSGL-1 signalling pathway reveals new therapeutic targets for disrupting leukocyte recruitment in inflammatory diseases.
-arrestin 1.
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