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In brief: February 2007Dendritic cells Deficiency of Bim in dendritic cells contributes to over-activation of lymphocytes and autoimmunity.
The B-cell lymphoma 2 (BCL-2) family of proteins regulates the mitochondrial apoptotic pathway, and BCL-2 homology 3 (BH3)-only proteins, such as BIM (BCL-2-interacting mediator of cell death), regulate the initiation stage of apoptosis. BIM-deficient mice develop spontaneous systemic autoimmunity with significant expansion of T-cell numbers; the authors investigated the role of dendritic cells (DCs) in this process. Compared with wild-type DCs, DCs from BIM-deficient mice showed increased survival, were more efficient at stimulating T-cell activation both in vivo and in vitro and were able to induce the production of autoantibodies following adoptive transfer. Therefore, BIM-deficient DCs might contribute to the development of autoimmunity and overactivation of T cells in BIM-deficient mice. Macrophages Regulation of IL-27 p28 gene expression in macrophages through MyD88- and interferon- Interleukin-27 (IL-27) is an IL-12-family member with both pro- and anti-inflammatory properties, and is composed of two subunits, Epstein–Barr virus-induced gene 3 (EBI3; also known as IL-27B) and p28. But how do inflammatory signals stimulate the production of IL-27? Liu et al. examined the transcriptional regulation of the p28 gene in mouse macrophages in response to lipopolysaccharide (LPS) and interferon- T-cell responses B and T lymphocyte attenuator regulates CD8+ T cell–intrinsic homeostasis and memory cell generation.
Accumulating data indicate that B- and T-lymphocyte attenuator (BTLA) is a negative regulator of T-cell activation, but its in vivo function is not clear. Consistent with its negative regulatory role, T cells from mice deficient in BTLA, or its ligand, were shown to be hyper-responsive. However, this was not due to loss of the co-inhibitory signal in the responding T cells but to increased numbers of CD8+ T cells with a memory phenotype, which are highly proliferative. Indeed, compared with wild-type T cells, BTLA-deficient T cells were more efficient generators of memory, although their response to antigen-specific priming was normal. Use of a competitive chimaera approach revealed that the loss of BTLA also results in enhanced homeostatic expansion. So, this study assigns two new roles for BTLA — regulation of T-cell memory formation and T-cell homeostasis. Antiviral immunity Regulation of innate antiviral defenses through a shared repressor domain in RIG-I and LGP2.
Retinoic-acid-inducible gene I (RIG-I) is an intracellular sensory molecule that binds double-stranded (ds) RNA. But how is RIG-I signalling controlled? In resting cells, RIG-I is maintained as a monomer, but following binding to dsRNA RIG-I self-associates to form a multimeric complex. RIG-I then interacts with interferon- Tumorigenesis Selective requirements for E2f3 in the development and tumorigenicity of Rb-deficient chimeric tissues Jacqueline Lees and colleagues have generated retinoblastoma 1 (Rb1)-/-;E2f3-/- chimeric mice to investigate how E2F3 influences tumorigenesis in Rb1-/- tissues, which was previously impossible because of Rb1-/-;E2f3-/- embryonic lethality. The authors show that the loss of E2f3 does not prevent the development of pituitary and thyroid tumours that result from Rb1 ablation. However, pre-neoplastic lesions that arise in Rb1-/- mice, which are thought to develop into the equivalent of human small-cell lung cancer, were completely suppressed by E2f3 inactivation. Therapy Targeting TACE-dependent EGFR ligand shedding in breast cancer Paraic Kenny and Mina Bissell show that the inhibition of tumour necrosis factor- Senescence The DNA damage signalling pathway is a critical mediator of oncogene-induced senescence Gerrado Ferbeyre and colleagues show that inhibition of a DNA-damage response kinase, ataxia telangiectasia mutated (ATM), in human fibroblasts prevents p53-dependent senescence induced by the oncogenes E2F1, RASV12 or STAT5 (signal transducer and activator of transcription 5). Oncogene-induced senescence (OIS) was associated with the activation of DNA-damage signalling pathways and could not be bypassed by the inactivation of TP53 or RB1, indicating that the DNA-damage response and OIS are functionally related barriers to tumorigenesis. Epigenetics H3K9 methylation and RNA interference regulate nucleolar organization and repeated DNA stability.
Using fly Su(var) mutants, in which heterochromatin formation and function are disrupted, the authors showed that a subset of these proteins, including a histone methyltransferase and HP1, are required for correct organization of nucleoli and satellite DNAs. Members of the RNAi pathway are also required, as revealed by the analysis of RNAi mutants. The authors also show that stability of repeated DNAs requires suppression of non-homologous end joining or other recombination pathways. Gene expression Genome-wide atlas of gene expression in the adult mouse brain.
In the past, examining gene expression in the brain involved studying a few genes histologically or many genes in large regions using microarrays. Knowledge of the expression of many genes at a much higher resolution is essential to characterize cellular populations. This high-throughput study, which is part of the Allen Institute for Brain Science Atlas project, describes the development of an anatomically comprehensive atlas of gene expression in the mouse brain. It details the expression patterns of more than 20,000 genes at cellular resolution and reveals that more than 80% of mouse genes are expressed in the brain. Neurodegenerative disorders Forebrain adenosine A2A receptors contribute to L-3,4-dihydroxyphenylalanine-induced dyskinesia in hemiparkinsonian mice.
Patients with Parkinson's disease sometimes develop L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID). Adenosine A2A receptor antagonists reduce symptoms in patients who have already developed LID. In a mouse model of Parkinson's disease, adenosine A2A receptor antagonists inhibited the development of symptoms of LID, and mice lacking forebrain adenosine A2A receptors displayed attenuated LID symptoms. These data provide evidence that adenosine A2A receptors contribute to LID and that they might be a novel pharmacological target. Food microbiology Lactobacillus acidophilus modulates intestinal pain and induces opioid and cannabinoid receptors The use of probiotics has been associated with alleviating the abdominal symptoms of irritable bowel syndrome. Rousseaux et al. speculated that this could occur if the probiotic bacteria induced the expression of analgesic receptors on intestinal epithelial cells. They found that the Lactobacillus acidophilus NCFM strain induced the expression of both an opioid receptor (MOR1) and a cannabinoid receptor (CB2) in a human epithelial cell line. The effects of L. acidophilus on the perception of visceral pain in vivo were examined in a rat model in which the pain threshold can be measured by analysing colorectal distention. The authors found that the oral administration of the NCFM strain had an analgesic effect that was similar to the analgesic effect of morphine. Proteomics A quantitative picture of the synaptic vesicle Using a battery of proteomics, biophysical, imaging and modeling technologies, Takamori et al. have constructed the first detailed, quantitative model of a trafficking organelle—the synaptic vesicle. They determined its size, density and mass, its full protein and lipid composition, and the copy numbers of major constituents. This complete model sets the stage for future quantitative trafficking studies. Takamori, S. et al. Spectroscopy Elementary insights into an enzyme mechanism Using a combination of colloidal probe atomic force microscopy and a quartz crystal microbalance, Suzuki et al. obtained an extremely detailed picture of the specific elementary interactions taking place in an enzymatic reaction. For the first time, they were able to investigate the complex interactions between the heptaprenyl disphosphate synthase enzyme subunits, a cofactor and a substrate. Suzuki, T. et al. | |
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-mediated pathways
B (NF-
-promoter stimulator 1 (IPS1) to signal to downstream effector molecules. This process was shown to be tightly regulated by an internal repressor domain. Indeed, deletion of this repressor domain resulted in constitutive signalling by RIG-I. The RIG-I-like RNA helicase LGP2 also contains a repressor domain, and it associates in trans with RIG-1 to prevent self-association. So, this study identifies a repressor domain in RIG-I and LGP2 that controls signalling to downstream effectors in response to dsRNA.
-converting enzyme (TACE) activity prevents an autocrine loop that normally leads to the shedding of a growth-factor ligand that functions as an oncogenic stimulus in a 3D tissue-culture model of breast cancer progression. TACE-dependent ligand shedding was shown to be active in breast cancer cell lines, and TACE expression in human breast tumour samples was indicative of poor prognosis. This could explain constitutive growth-factor receptor activity without mutations in the corresponding genes, and provides a new oncogenic pathway worth targeting for anticancer drug development.