| |||
|
|
|||
|
      |
|
 |
|
| |||||||||||
| |||||||||||
| |||||||||||
| | | | ||||||||
|
In brief: December 2007Lipid trafficking SNARE proteins mediate fusion between cytosolic lipid droplets and are implicated in insulin sensitivity. Lipid droplets are dynamic intracellular stores for neutral lipids. A team led by Sven-Olof Olofsson now shows that cytosolic lipid droplets are associated with three SNARE proteins (VAMP4, syntaxin-5 and SNAP23), which are components of the machinery that drives membrane bilayer fusion. Knockdown of these SNAREs decreases droplet fusion rate and size, suggesting a role for the SNARE system in fusing lipid monolayers as well as bilayers. They also implicate SNAP23 in fatty-acid-induced insulin resistance in cells. Infectious disease Blockade of NKG2D on NKT cells prevents hepatitis and the acute response to hepatitis B virus.
Understanding the immunopathogenesis of liver disease following infection with hepatitis B virus (HBV) is important for the development of new therapeutics. The authors previously established mouse models of primary HBV infection in which non-classical natural killer T (NKT) cells that do not recognize the classical NKT-cell ligand Mathematical models Network analysis of oncogenic Ras activation in cancer Mutation of Ras is a common occurrence in many human tumours. To understand more about the many pathways that mutated Ras can affect, Edward Stites and colleagues developed a mathematical model of Ras signalling. Their model and subsequent in vitro experiments indicate why only point mutations that render Ras insensitive to GTPase activating protein are commonly found in human tumours. Moreover, their model predicted novel drugs that might inhibit the cancerous Ras network more effectively than the wild-type network. Cancer symptoms Tumor-induced anorexia and weight loss are mediated by the TGF- Patients with late-stage cancer often experience a wasting syndrome that includes anorexia and weight loss. Although this is thought to be cytokine-mediated, Johnen et al. now demonstrate a direct connection between levels of macrophage inhibitory cytokine 1 (MIC1) and cancer-associated weight loss in both humans with prostate cancer and mice with xenografted prostate tumours. Weight loss could be reversed in mice with tumours using an antibody against MIC1, and normal mice that were given systemic MIC1 had reduced body weight. Cancer stem cells Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4 Todaro et al. have shown that cells from primary human colon tumours that express the stem-cell marker CD133 are both necessary and sufficient to form subcutaneous tumours in immunodeficient mice. The CD133+ cells were resistant to death induced by various chemotherapeutic drugs, and the authors showed that this was because of interleukin 4 (IL4) produced by the CD133+ cells. Consistent with this, treatment of mice with an IL4-neutralizing antibody or an IL4 receptor- Cancer An elaborate pathway required for Ras-mediated epigenetic silencing. A genome-wide RNAi screen in human cancer cells in culture identifies a network of genes that converts a normal cell to a cancerous one. KRAS-transformed cells were screened for epigenetic regulators in the Ras pathway that silence the pro-apoptotic gene FAS. The 28 epigenetic modifiers — most of which were not previously connected to Ras — belong to a common pathway of 'Ras epigenetic silencing factors' that also silence other, unrelated genes that are required for cell transformation. Neurotrophins Roles for the pro-neurotrophin receptor sortilin in neuronal development, aging and brain injury Pro-neurotrophins are known to induce apoptosis through a sortilin–p75NTR-dependent cell-death pathway. Here, the authors examined the effects of sortilin on neuronal viability in sortilin-knockout mice. Although apoptosis in the developing retina was reduced, the developmentally regulated apoptosis of sympathetic neurons was not affected. Interestingly, these cells were protected from age-dependent degeneration and cell death after injury, highlighting a pro-apoptotic function of sortilin beyond the development of the nervous system. Neurological disorders ERK activation causes epilepsy by stimulating NMDA receptor activity In this study, conditional expression of constitutively active (ca) MEK1 (MAP/ERK kinase 1) in the mouse brain was found to trigger spontaneous epileptic seizures, indicating a role for ERK–MAPK signalling in the aetiology of this neurological disorder. caMEK1 increased the expression of NMDA receptor 2B (NR2B) in an ERK-dependent manner, and pharmacological inhibition of NR2B abrogated epilepsy in vivo. NR2B could hence be a new target for anti-epileptic drugs. Vaccines Adjuvanting a DNA vaccine with a TLR9 ligand plus Flt3 ligand results in enhanced cellular immunity against the simian immunodeficiency virus In this report, Kwissa and colleagues examined the efficacy of Toll-like receptor (TLR) ligands on augmenting the immunogenicity of a DNA prime–boost vaccine against simian immunodeficiency virus (SIV). They injected rhesus macaques with FMS-like tyrosine kinase 3 ligand (FLT3L) to expand dendritic cells (DCs), and primed them with a DNA vaccine encoding immunodeficiency virus antigens mixed with ligands for TLR9 or TLR7 and TLR8. The animals were then boosted with DNA and twice with recombinant modified vaccinia virus Ankara that expressed the same antigens. Activating DCs with TLR9 ligand during the initial immunization with a DNA vaccine resulted in an enhanced antigen-specific CD8+ T-cell response and improved control of viral loads after challenge with SIV. | |
| ||||||||
| |||||||||||
 | |||||||||||
| |||||||||||
| |||||||||||
| |||||||||||
HOME | SIGNALING UPDATE | MOLECULE PAGES | DATA CENTER | ABOUT US | |||||||||||
| |||||||||||
-galactosylceramide were shown to be sufficient to induce hepatitis. In the present study, the role of the NK- and NKT-cell activating receptor NKG2D in hepatitis was addressed. Surface expression of NKG2D by NK and NKT cells and of the NKG2D ligand RAE1 (retinoic acid early transcript 1) by hepatocytes was modulated during acute infection, and blockade of the NKG2D–ligand interaction prevented acute hepatitis and liver injury. The results support a model in which non-classical NKT cells are activated by HBV infection, leading to the production of cytokines that then activate NK cells.
superfamily cytokine MIC-1