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In brief: October 2007Post-translational modification SUMO-targeted ubiquitin ligases in genome stability Conserved function of RNF4 family proteins in eukaryotes: targeting a ubiquitin ligase to SUMOylated proteins Both groups identified a family of SUMO-targeted ubiquitin (Ub) ligases (STUbLs) that contain a SUMO-interacting motif, through which STUbLs are recruited to sumoylated proteins, and a RING-finger domain. Mammalian RNF4 is an E3 Ub ligase, whereas the Schizosaccharomyces pombe proteins Rfp1 and Rfp2 each heterodimerize with Slx8, which has Ub ligase activity. Cells that lack Rfp1/2–Slx8 have genomic instability, are hypersensitive to genotoxic stress and accumulate sumoylated proteins. Expression of mammalian RNF4 rescued the mutant phenotype, which demonstrates the functional conservation of STUbLs. The mutant phenotype was also suppressed by deletion of the SUMO ligase Pli1, which suggests that STUbLs regulate homeostasis of the SUMO pathway. MicroRNA MicroRNA control of Nodal signalling Target protectors reveal dampening and balancing of Nodal agonist and antagonist by miR-430 Martello et al. showed that the microRNAs miR-15 and miR-16 negatively regulate signalling through the transforming growth factor- Dendritic cells BDCA2/Fc Human plasmacytoid dendritic cells (pDCs) express a C-type lectin called BDCA2 (blood DC antigen 2), which lacks an identifiable signalling motif. BDCA2 is known to be a potent regulator of pDC function, although how it transduces signals is unknown. Here, Lanier, Liu and colleagues show that BDCA2 signals in pDCs by forming a complex with the transmembrane adaptor protein FceRI Metastasis Activation of the RalGEF/Ral pathway promotes prostate cancer metastasis to bone Little is known about the pathways that control organ-specific metastasis. Yin et al. show that activated HRAS (HRASV12)-induced metastasis of a normally non-metastatic human prostate cancer cell line (DU145) to different organs in mice requires different signalling pathways downstream of HRASV12. Using different HRAS effector mutants, the authors found that the Raf–ERK (extracellular signal-regulated kinase) pathway controlled metastasis to the brain, whereas activation of Ral guanine nucleotide exchange factors (RalGEFs) caused metastasis to bone, the most frequent site of prostate cancer metastases. Loss of RALA also inhibited bone metastasis of a metastatic prostate cancer cell line (PC3) by blocking growth at the secondary site but not homing or initial colonization. Therapy Death-receptor O-glycosylation controls tumour-cell sensitivity to the proapoptotic ligand Apo2L/TRAIL Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce apoptosis of cancer cells through its receptors death receptor 4 (DR4) and DR5. Although TRAIL is being developed as an anticancer therapy, it is not known why some cancers respond to this agent and others do not. Wagner et al. found that expression of the peptidyl O-glycosyltransferase GALNT14 correlated with TRAIL sensitivity in cancer cell lines, and about 30% of samples of various human tumour types had GALNT14 overexpression. Knockdown of GALNT14 in cell lines using small interfering RNA reduces TRAIL sensitivity, and O-glycosylation of DR4 and DR5 seems to be required for apoptotic signalling. These data indicate that O-glycosylation and GALNT14 expression could possibly serve as predictive biomarkers for the efficacy of TRAIL-based therapy. Leukaemia Cytokine-dependent imatinib resistance in mouse BCR-ABL+, Arf-null lymphoblastic leukemia Williams et al. show that expression of the oncogenic fusion protein BCR-ABL in mouse pre-B cells lacking the tumour suppressor ARF causes highly aggressive acute lymphocytic leukaemia (ALL) when the cells are intravenously inoculated into healthy syngeneic mice. These leukaemias are resistant to therapy with the BCR-ABL tyrosine kinase inhibitor imatinib, but recovered cells are sensitive, indicating that the resistance is non-tumour-cell-autonomous. If the pre-B cells also lack the cytokine receptor common Gene regulation Domain-wide regulation of gene expression in the human genome Transcriptomics has shown that human and mouse genomes contain many distinct clusters of either highly expressed or weakly expressed genes. This study provides the first evidence that residence in such domains contributes to the expression levels of genes. The expression of a GFP reporter construct that was integrated at 90 different positions correlated with the activity of the domains into which it was inserted. So, both regulation of individual genes by transcription factor complexes and domain-wide regulation seem to contribute to gene expression patterns in mammalian genomes. Developmental biology Wnt signaling mediates regional specification in the vertebrate face This paper reports that the regional specification of the vertebrate face and the changes in face morphology that occur during evolution depend on the distribution of Wnt signalling during embryonic development. During embryogenesis, Wnt signalling is active in face regions that protrude at later stages, corresponding to areas of cell proliferation. Mice in which Wnt signalling was disrupted had a flatter midface and more widely set eyes. The fact that a similar treatment had comparable consequences in chicks suggests that the distribution of Wnt signalling determines species-specific facial features. Molecular neuroscience Extracellular stimuli specifically regulate localized levels of individual neuronal mRNAs Localized protein synthesis enables neurons to respond rapidly to changes in the environment. Here, the authors examined the effects of both growth-promoting and growth-inhibiting ligands on the localization of a broad population of mRNAs in regenerating sensory neurons. They found that these extracellular factors differentially regulate the transport of specific mRNAs from the cell body to subcellular regions adjacent to the ligand source, thus influencing local protein synthesis. Neurodegenerative disease HIV/gp120 decreases adult neural progenitor cell proliferation via checkpoint kinase-mediated cell-cycle withdrawal and G1 arrest HIV-associated dementia (HAD) has been associated with reduced hippocampal neurogenesis, but the underlying molecular mechanisms are unclear. The authors showed that the HIV-envelope glycoprotein gp120, which is known to contribute to HAD pathology, reduced the proliferation of neural progenitor cells in vitro and in vivo by prolonging the G1 phase of the cell cycle. They also demonstrated the involvement of a signalling cascade comprising MAPK, MAPK-activated protein-kinase 2 and Cdc25B/C activities in these effects, providing new information on the molecular mechanisms that underlie HAD. G-protein-coupled receptors Nongenomic actions of bile acids. Synthesis and preliminary characterization of 23- and 6,23-akyl-substituted bile acid derivatives as selective modulators for the G-protein coupled receptor TGR5 TGR5, a G-protein-coupled receptor for bile acid, is a promising target for metabolic control but no selective and potent ligands are available. Pellicciari and colleagues identified alkyl-substituted derivatives of chenodeoxycholic acid that were potent and selective agonists of TGR5. Methylation at the C-23(S) position of natural bile acids conferred selectivity for TGR5 over the nuclear receptor for bile acids. These results show for the first time a pharmacological differentiation of genomic versus nongenomic effects mediated by bile-acid derivatives. Protein biochemistry Genetic selection with tunable stringency Selection schemes are often based on complementation of a metabolic defect in a model microorganism. Kleeb et al. now design flexible stringency selection by adopting strategies similar to those that control metabolic flux in vivo. By providing variable amounts of an enzyme that shunts a given metabolite down an alternative pathway in shikimate biosynthesis, they were able to select for bacterial dehydratases with activities over a 50,000-fold range. Virology Poliovirus entry into human brain microvascular cells requires receptor-induced activation of SHP-2 Human brain microvascular endothelial cells (HBMECs) retain many of the characteristics of brain endothelial cells, and so provide a useful model system to study how pathogens, such as poliovirus, cross the blood–brain barrier. The poliovirus receptor was found to be necessary for poliovirus infection of HBMECs and it was shown that poliovirus enters HBMECs by dynamin-dependent caveolar endocytosis. Detailed analysis of the downstream events that follow demonstrated that the virus–receptor interaction triggers intracellular signals that are essential for virus entry, including actin rearrangements and activation of the protein tyrosine phosphatase SHP-2. | |
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(TGF
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complex signals through a novel BCR-like pathway in human plasmacytoid dendritic cells