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871.
D Sidransky T Mikkelsen K Schwechheimer M L Rosenblum W Cavanee B Vogelstein 《Nature》1992,355(6363):846-847
Tumour progression is a fundamental feature of the biology of cancer. Cancers do not arise de novo in their final form, but begin as small, indolent growths, which gradually acquire characteristics associated with malignancy. In the brain, for example, low-grade tumours (astrocytomas) evolve into faster growing, more dysplastic and invasive high-grade tumours (glioblastomas). To define the genetic events underlying brain tumour progression, we analysed the p53 gene in ten primary brain tumour pairs. Seven pairs consisted of tumours that were high grade both at presentation and recurrence (group A) and three pairs consisted of low-grade tumours that had progressed to higher grade tumours (group B). In group A pairs, four of the recurrent tumours contained a p53 gene mutation; in three of them, the same mutation was found in the primary tumour. In group B pairs, progression to high grade was associated with a p53 gene mutation. A subpopulation of cells were present in the low-grade tumours that contained the same p53 gene mutation predominant in the cells of the recurrent tumours that had progressed to glioblastoma. Thus, the histological progression of brain tumours was associated with a clonal expansion of cells that had previously acquired a mutation in the p53 gene, endowing them with a selective growth advantage. These experimental observations strongly support Nowell's clonal evolution model of tumour progression. 相似文献
872.
Dynamin was initially identified in calf brain tissue as a protein of relative molecular mass 100,000 which induced nucleotide-sensitive bundling of microtubules. Purified dynamin showed only trace ATPase activity. But in combination with an activating factor removed during the purification, it exhibited microtubule-activated ATPase activity and dynamin-induced bundles showed evidence of ATP-dependent force production. Dynamin is the product of the Drosophila gene shibire, which has been implicated in synaptic vesicle recycling and, more generally, in the budding of endocytic vesicles from the plasma membrane. Dynamin also shows extensive homology with proteins that participate in vacuolar protein sorting and spindle pole-body separation in yeast, and in interferon-induced viral resistance in mammals. All members of this family contain consensus sequence elements consistent with GTP binding near their amino termini, although none has been shown to have GTPase activity. We report here that dynamin is a specific GTPase which can be stimulated to very high levels of activity by microtubules. 相似文献
873.
874.
Regulatory GTP-binding proteins (G proteins) are membrane-attached heterotrimers (alpha, beta, gamma) that mediate cellular responses to a wide variety of extracellular stimuli. They undergo a cycle of guanine-nucleotide exchange and GTP hydrolysis, during which they dissociate into alpha-subunit and beta gamma complex. The roles of G-protein alpha-subunits in these processes and for the specificity of signal transduction are largely established; the beta- and gamma-subunits are essential for receptor-induced G-protein activation and seem to be less diverse and less specific. Although the complementary DNAs for several beta-subunits have been cloned, isolated subunits have only been studied as beta gamma complexes. Functional differences have been ascribed to the gamma-subunit on the basis of extensive sequence similarity among beta-subunits and apparent heterogeneity in gamma-subunit sequences. Beta gamma complexes can interact directly or indirectly with different effectors. They seem to be interchangeable in their interaction with pertussis toxin-sensitive alpha-subunits, so we tested this by microinjecting antisense oligonucleotides into nuclei of a rat pituitary cell line to suppress the synthesis of individual beta-subunits selectively. Here we show that two out of four subtypes of beta-subunits tested (beta 1 and beta 3) are selectively involved in the signal transduction cascades from muscarinic M4 (ref. 4) and somatostatin receptors, respectively, to voltage-dependent Ca2+ channels. 相似文献
875.
Human aminopeptidase N is a receptor for human coronavirus 229E. 总被引:62,自引:0,他引:62
C L Yeager R A Ashmun R K Williams C B Cardellichio L H Shapiro A T Look K V Holmes 《Nature》1992,357(6377):420-422
Human coronaviruses (HCV) in two serogroups represented by HCV-229E and HCV-OC43 are an important cause of upper respiratory tract infections. Here we report that human aminopeptidase N, a cell-surface metalloprotease on intestinal, lung and kidney epithelial cells, is a receptor for human coronavirus strain HCV-229E, but not for HCV-OC43. A monoclonal antibody, RBS, blocked HCV-229E virus infection of human lung fibroblasts, immunoprecipitated aminopeptidase N and inhibited its enzymatic activity. HCV-229E-resistant murine fibroblasts became susceptible after transfection with complementary DNA encoding human aminopeptidase N. By contrast, infection of human cells with HCV-OC43 was not inhibited by antibody RBS and expression of aminopeptidase N did not enhance HCV-OC43 replication in mouse cells. A mutant aminopeptidase lacking the catalytic site of the enzyme did not bind HCV-229E or RBS and did not render murine cells susceptible to HCV-229E infection, suggesting that the virus-binding site may lie at or near the active site of the human aminopeptidase molecule. 相似文献
876.
Neural subsystems for object knowledge. 总被引:6,自引:0,他引:6
Critical issues in the cognitive neuroscience of language are whether there are multiple systems for the representation of meaning, perhaps organized by processing system (such as vision or language), and whether further subsystems are distinguishable within these larger ones. We describe here a patient (K.R.) with cerebral damage whose pattern of acquired deficits offers direct evidence for a major division between visually based and language-based higher-level representations, and for processing subsystems within language. K.R. could not name animals regardless of the type of presentation (auditory or visual), but had no difficulty naming other living things and objects. When asked to describe verbally the physical attributes of animals (for example, 'what colour is an elephant?'), she was strikingly impaired. Nevertheless, she could distinguish the correct physical attributes of animals when they were presented visually (she could distinguish animals that were correctly coloured from those that were not). Her knowledge of input stimulus. To explain this selective deficit, these data mandate the existence of two distinct representations of such properties in normal individuals, one visually based and one language-based. Furthermore, these data establish that knowledge of physical attributes is strictly segregated from knowledge of other properties in the language system. 相似文献
877.
Protein kinase C reduces Mg2+ block of NMDA-receptor channels as a mechanism of modulation. 总被引:42,自引:0,他引:42
The roles of N-methyl-D-aspartate (NMDA) receptors and protein kinase C (PKC) are critical in generating and maintaining a variety of sustained neuronal responses. In the nociceptive (pain-sensing) system, tissue injury or repetitive stimulation of small-diameter afferent fibres triggers a dramatic increase in discharge (wind-up) or prolonged depolarization of spinal cord neurons. This central sensitization can neither be induced nor maintained when NMDA receptor channels are blocked. In the trigeminal subnucleus caudalis (a centre for processing nociceptive information from the orofacial areas), a mu-opioid receptor agonist causes a sustained increase in NMDA-activated currents by activating intracellular PKC. There is also evidence that PKC enhances NMDA-receptor-mediated glutamate responses and regulates long-term potentiation of synaptic transmission. Despite the importance of NMDA-receptors and PKC, the mechanism by which PKC alters the NMDA response has remained unclear. Here we examine the actions of intracellularly applied PKC on NMDA-activated currents in isolated trigeminal neurons. We find that PKC potentiates the NMDA response by increasing the probability of channel openings and by reducing the voltage-dependent Mg2+ block of NMDA-receptor channels. 相似文献
878.
In polarized neurons, axons and dendrites perform different functions, which are reflected in their different molecular organization. Studies on the sorting of viral and endogenous glycoproteins in epithelial cells and hippocampal neurons suggest that there may be similarities in the mechanism of sorting in these two cell types. The mechanisms that maintain the distinct composition of the two plasma membrane domains in these two cell types must, however, be different. We have proposed the existence of a functional barrier at the axonal hillock/initial segment which prevents the intermixing of membrane constituents. Here we test this hypothesis by fusing liposomes containing fluorescent phospholipids into the plasma membrane of polarized hippocampal cells in culture. Fusion was induced by lowering the pH and mediated by influenza virus haemagglutinin expressed on the axonal surface of neurons infected with fowl plague virus. Labelling was found exclusively on axons after fusion. Although the fused lipids were mobile on the axonal membrane, no labelling was detected on the cell body and dendritic surfaces. These results suggest that there is a diffusion barrier at the axonal hillock/initial segment which maintains the compositional differences between the axonal and somatodendritic domains. 相似文献
879.
Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases beta-protein production. 总被引:41,自引:0,他引:41
M Citron T Oltersdorf C Haass L McConlogue A Y Hung P Seubert C Vigo-Pelfrey I Lieberburg D J Selkoe 《Nature》1992,360(6405):672-674
Progressive cerebral deposition of the 39-43-amino-acid amyloid beta-protein (A beta) is an invariant feature of Alzheimer's disease which precedes symptoms of dementia by years or decades. The only specific molecular defects that cause Alzheimer's disease which have been identified so far are missense mutations in the gene encoding the beta-amyloid precursor protein (beta-APP) in certain families with an autosomal dominant form of the disease (familial Alzheimer's disease, or FAD). These mutations are located within or immediately flanking the A beta region of beta-APP, but the mechanism by which they cause the pathological phenotype of early and accelerated A beta deposition is unknown. Here we report that cultured cells which express a beta-APP complementary DNA bearing a double mutation (Lys to Asn at residue 595 plus Met to Leu at position 596) found in a Swedish FAD family produce approximately 6-8-fold more A beta than cells expressing normal beta-APP. The Met 596 to Leu mutation is principally responsible for the increase. These data establish a direct link between a FAD genotype and the clinicopathological phenotype. Further, they confirm the relevance of the continuous A beta production by cultured cells for elucidating the fundamental mechanism of Alzheimer's disease. 相似文献
880.
Tyrosine phosphorylation of vav proto-oncogene product containing SH2 domain and transcription factor motifs. 总被引:30,自引:0,他引:30
B Margolis P Hu S Katzav W Li J M Oliver A Ullrich A Weiss J Schlessinger 《Nature》1992,356(6364):71-74