| |||
|
|
|||
|
      |
|
 |
|
| |||||||||||
| |||||||||||
| |||||||||||
| | | | ||||||||
|
In brief: June 2004Cell death Alkylating DNA damage stimulates a
regulated form of necrotic cell death Necrosis has been regarded as an unregulated form of cell death. But, Craig Thompson and colleagues now show that this is not the case. They found that alkylating agents induce necrotic cell death in apoptosis-deficient cells, and that this requires the activation of the DNA-repair protein poly(ADP-ribose) polymerase (PARP). In cells that use mainly aerobic glycolysis for their ATP production — such as proliferating cells, including cancer cells — PARP triggers the depletion of ATP, which causes subsequent necrosis. Cell cycle A role for the FEAR pathway in nuclear
positioning during anaphase Separase (Esp1 in budding yeast) triggers sister-chromatid separation in anaphase. Interestingly, in the absence of Esp1 function, the undivided nucleus is inherited almost exclusively by the daughter cell. So what causes the daughter-cell preference? These authors show that, independent of its role in sister-chromatid segregation, Esp1 affects nuclear positioning as part of the FEAR (Cdc14 early anaphase release) pathway, which induces a mother-cell-directed pulling force on the spindle poles. Protein modification S-Nitrosylation of parkin regulates
ubiquitination and compromises parkin's protective function Parkin is an E3 ubiquitin ligase that ubiquitinates substrates that are important for dopamine-neuron survival. Mutations in parkin that disrupt its enzymatic activity are the most common cause of hereditary Parkinson's disease (PD). Chung et al. now show that parkin is S-nitrosylated in vitro and in vivo in animal models of PD and in the brains of PD patients. S-nitrosylation of parkin inhibits its E3 ubiquitin ligase activity and its protective function, and so might contribute to the neurodegeneration process. Structure Supine orientation of a murine MHC
class I molecule on the membrane bilayer Previous studies looking at the structure of MHC molecules have used recombinant forms consisting of only the extracellular domains. However, these structures do not take into account interactions with specific lipid microdomains of the plasma membrane. To address this, Luc Teyton and colleagues used electron microscopy to analyse the extracellular domains of the MHC class I molecule H–2Kb tethered to a lipid bilayer by a histidine tag. Surprisingly, the MHC molecule was shown to lie on its side parallel to the membrane, rather than standing up perpendicular to the membrane as is usually depicted. This orientation is maintained by ionic interactions between lipid head groups in the membrane and the length of the MHC protein. As the supine orientation was shown to be optimal for binding of the co-receptor CD8, changes in MHC orientation might be another way to regulate T-cell-receptor signalling. Signalling The cell-surface receptor SLAM controls
T cell and macrophage functions In this study, mice deficient for signalling lymphocyte activation molecule (SLAM, also known as CD150) were generated and used to analyse the specific contribution of SLAM to immune responses. SLAM-mediated signalling occurs through SLAM-associated protein (SAP), and SAP-deficient mice have a severe X-linked immunodeficiency. As SAP also mediates signalling through five other SLAM-related receptors, the precise contribution of SLAM to the immunodeficiency was unknown. The SLAM-deficient mice had impaired macrophage responses to lipopolysaccharide and increased susceptibility to infection with Leishmania major, as well as defective TH2-cell responses. This indicates that SLAM functions as a co-receptor for signalling through Toll-like receptor 4 and the T-cell receptor. Innate Immunity Nucleic acid is a novel ligand for
innate immune pattern recognition collectins surfactant proteins A and
D and mannose-binding lectin Collectins, including surfactant protein D (SP-D), are extracellular innate immune proteins known to bind microbial carbohydrate patterns. In this study, SP-D was shown to bind linear plasmid DNA directly, as well as synthetic oligonucleotides, even at high salt concentrations. Whereas this strong interaction was mediated largely by the collagen-like region of SP-D, electron microscopy indicated that the globular regions of the molecule also associated with DNA. Furthermore, because SP-D co-localized with the DNA of apoptotic cells, the authors suggest that SP-D functions as an opsonin, binding the DNA of apoptotic cells to enhance their clearance. Antigen Presentation CD1d function is regulated by microsomal
triglyceride transfer protein The MHC-class-I-like molecule CD1d presents glycolipid antigens to natural killer T (NKT) cells, and this study investigated the role of microsomal triglyceride-transfer protein (MTP) — an endoplasmic-reticulum (ER)-resident lipid-transfer protein — in CD1d function. In hepatocytes lacking MTP, CD1d accumulated in the ER and cell-surface expression was reduced. Consequently, endogenous and exogenous glycolipid antigen presentation was impaired. Similar observations were obtained using an intestinal epithelial-cell line, providing evidence for a general role for MTP in CD1d trafficking and antigen presentation. Because the MTP defect led to resistance to NKT-cell-mediated hepatocyte injury and colitis, the authors suggest that MTP blockade might be of clinical benefit in NKT-cell-mediated immunopathologies. Metastasis Hypoxia induces adhesion molecules
on cancer cells: a missing link between Warburg effect and induction of
selectin-ligand carbohydrates Metastatic spread through blood vessels requires tumour cells to express carbohydrate selectin ligands that mediate their adhesion to endothelial cells, allowing them to enter the vasculature. Koike et al. show that hypoxia induces increased expression of selectin ligands and the enzymes involved in their synthesis in colon cancer cells, and that this requires hypoxia-inducible transcription factors. Therapeutics Suramin inhibits death receptor-induced
apoptosis in vitro and fulminant apoptotic liver damage in mice
Suramin, a derivative of urea, is a chemotherapeutic agent, but its effect on apoptosis is unknown. Eichhorst et al. show that suramin inhibits CD95-mediated cell death and under certain circumstances will inhibit chemotherapy-induced apoptosis. This indicates that the use of suramin as a chemotherapeutic agent — based on its ability to inhibit cytokine signalling — needs to be re-evaluated. Plant Genetics A Ca2+/calmodulin-dependent
protein kinase required for symbiotic nodule development: gene identification
by transcript-based cloning Because of their often large and complex genomes, mapping mutations in crop plants by positional cloning can be a painstaking process. Raka Mitra and colleagues have successfully used transcript abundance to clone the Medicago dmi3 gene, which is involved in symbiotic nodule development. Importantly, they show that the method is valid in barley, and by extension, could be useful in many crop plants. Pharmacogenetics
EGFR mutations in lung cancer: correlation with clinical response to Gefitnib therapy
Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to Gefitinib
Most patients with non-small cell lung cancer do not respond to the tyrosine kinase inhibitor gefitinib (Iressa; AstraZeneca), although those who do often have a dramatic clinical response. Two recent studies have identified similar point or deletion mutations in the epidermal growth factor receptor (EGFR) that could be predictive of which patients will benefit from gefitinib. Tumour biopsies from eight out of nine patients with gefitinib-responsive lung cancer carried these mutations, compared with none from seven non-responders. Paez et al. found EGFR mutations in 15 of 58 unselected tumours from Japan and 1 of 61 from the United States. Five out of five samples selected that had EGFR mutations were from treatment responders. The mutations are found in the ATP-binding pocket of the tyrosine kinase domain of EGFR and are associated with increased sensitivity to inhibition by gefitinib. | |
| ||||||||
| |||||||||||
 | |||||||||||
| |||||||||||
| |||||||||||
| |||||||||||
HOME | SIGNALING UPDATE | MOLECULE PAGES | DATA CENTER | ABOUT US | |||||||||||
| |||||||||||
