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High-throughput retroviral tagging to identify components of specific signaling pathways in cancer 总被引:17,自引:0,他引:17
Mikkers H Allen J Knipscheer P Romeijn L Hart A Vink E Berns A Romeyn L 《Nature genetics》2002,32(1):153-159
Genetic screens carried out in lower organisms such as yeast, Drosophila melanogaster and Caenorhabditis elegans have revealed many signaling pathways. For example, components of the RAS signaling cascade were identified using a mutant eye phenotype in D. melanogaster as a readout. Screening is usually based on enhancing or suppressing a phenotype by way of a known mutation in a particular signaling pathway. Such in vivo screens have been difficult to carry out in mammals, however, owing to their relatively long generation times and the limited number of animals that can be screened. Here we describe an in vivo mammalian genetic screen used to identify components of pathways contributing to oncogenic transformation. We applied retroviral insertional mutagenesis in Myc transgenic (E mu Myc) mice lacking expression of Pim1 and Pim2 to search for genes that can substitute for Pim1 and Pim2 in lymphomagenesis. We determined the chromosomal positions of 477 retroviral insertion sites (RISs) derived from 38 tumors from E mu Myc Pim1(-/-) Pim2(-/-) mice and 27 tumors from E mu Myc control mice using the Ensembl and Celera annotated mouse genome databases. There were 52 sites occupied by proviruses in more than one tumor. These common insertion sites (CISs) are likely to contain genes contributing to tumorigenesis. Comparison of the RISs in tumors of Pim-null mice with the RISs in tumors of E mu Myc control mice indicated that 10 of the 52 CISs belong to the Pim complementation group. In addition, we found that Pim3 is selectively activated in Pim-null tumor cells, which supports the validity of our approach. 相似文献
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Guard cells are located in the epidermis of plant leaves, and in pairs surround stomatal pores. These control both the influx of CO2 as a raw material for photosynthesis and water loss from plants through transpiration to the atmosphere. Guard cells have become a highly developed system for dissecting early signal transduction mechanisms in plants. In response to drought, plants synthesize the hormone abscisic acid, which triggers closing of stomata, thus reducing water loss. Recently, central regulators of guard cell abscisic acid signalling have been discovered. The molecular understanding of the guard cell signal transduction network opens possibilities for engineering stomatal responses to control CO2 intake and plant water loss. 相似文献
25.
Loss of neuropathy target esterase in mice links organophosphate exposure to hyperactivity 总被引:13,自引:0,他引:13
Neuropathy target esterase (NTE) is involved in neural development and is the target for neurodegeneration induced by selected organophosphorus pesticides and chemical warfare agents. We generated mice with disruptions in Nte, the gene encoding NTE. Nte(-/-) mice die after embryonic day 8, and Nte(+/-) mice have lower activity of Nte in the brain and higher mortality when exposed to the Nte-inhibiting compound ethyl octylphosphonofluoridate (EOPF) than do wild-type mice. Nte(+/-) and wild-type mice treated with 1 mg per kg of body weight of EOPF have elevated motor activity, showing that even minor reduction of Nte activity leads to hyperactivity. These studies show that genetic or chemical reduction of Nte activity results in a neurological phenotype of hyperactivity in mammals and indicate that EOPF toxicity occurs directly through inhibition of Nte without the requirement for Nte gain of function or aging. 相似文献
26.
Mutations in the gene encoding peroxisomal alpha-methylacyl-CoA racemase cause adult-onset sensory motor neuropathy 总被引:12,自引:0,他引:12
Ferdinandusse S Denis S Clayton PT Graham A Rees JE Allen JT McLean BN Brown AY Vreken P Waterham HR Wanders RJ 《Nature genetics》2000,24(2):188-191
Sensory motor neuropathy is associated with various inherited disorders including Charcot-Marie-Tooth disease, X-linked adrenoleukodystrophy/adrenomyeloneuropathy and Refsum disease. In the latter two, the neuropathy is thought to result from the accumulation of specific fatty acids. We describe here three patients with elevated plasma concentrations of pristanic acid (a branched-chain fatty acid) and C27-bile-acid intermediates. Two of the patients suffered from adult-onset sensory motor neuropathy. One patient also had pigmentary retinopathy, suggesting Refsum disease, whereas the other patient had upper motor neuron signs in the legs, suggesting adrenomyeloneuropathy. The third patient was a child without neuropathy. In all three patients we discovered a deficiency of alpha-methylacyl-CoA racemase (AMACR). This enzyme is responsible for the conversion of pristanoyl-CoA and C27-bile acyl-CoAs to their (S)-stereoisomers, which are the only stereoisomers that can be degraded via peroxisomal beta-oxidation. Sequence analysis of AMACR cDNA from the patients identified two different mutations that are likely to cause disease, based on analysis in Escherichia coli. Our findings have implications for the diagnosis of adult-onset neuropathies of unknown aetiology. 相似文献
27.
Tat-specific cytotoxic T lymphocytes select for SIV escape variants during resolution of primary viraemia 总被引:55,自引:0,他引:55
Allen TM O'Connor DH Jing P Dzuris JL Mothé BR Vogel TU Dunphy E Liebl ME Emerson C Wilson N Kunstman KJ Wang X Allison DB Hughes AL Desrosiers RC Altman JD Wolinsky SM Sette A Watkins DI 《Nature》2000,407(6802):386-390
Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections are characterized by early peaks of viraemia that decline as strong cellular immune responses develop. Although it has been shown that virus-specific CD8-positive cytotoxic T lymphocytes (CTLs) exert selective pressure during HIV and SIV infection, the data have been controversial. Here we show that Tat-specific CD8-positive T-lymphocyte responses select for new viral escape variants during the acute phase of infection. We sequenced the entire virus immediately after the acute phase, and found that amino-acid replacements accumulated primarily in Tat CTL epitopes. This implies that Tat-specific CTLs may be significantly involved in controlling wild-type virus replication, and suggests that responses against viral proteins that are expressed early during the viral life cycle might be attractive targets for HIV vaccine development. 相似文献
28.
Allen Stairs Jeffrey Bub 《Studies in History and Philosophy of Science Part B: Studies in History and Philosophy of Modern Physics》2007,38(4):863-878
James D. Malley and Arthur Fine have argued that interest in noncontextual hidden variable theories is misplaced because at bottom such theories are simply attempts to turn noncommuting quantities into commuting ones. We disagree and argue that the issues are richer and more complex. 相似文献
29.
We counted kokanee spawners and carcasses every 1-7 days from mid-September through mid-November in 1991 and 1992 in Taylor Creek, a tributary to Lake Tahoe, California-Nevada. Less than 1% of the spawning run entered Taylor Creek before flow from Fallen Leaf Lake was increased on 2 October 1991; in 1992 the peak occurred on 30 September or 1 October after flows increased on 29 September. In both years spawners concentrated in the middle three of five stream reaches below the impassable Fallen Leaf Lake dam. From tab-and-recovery experiments, the average longevity of male spawners in the stream was 3.5 days in 1991 and 2.8 days in 1992, whereas the average female longevity was 2.0 days in 1991 and 2.3 days in 1992. Observed carcasses accounted for less than 10% of spawners counted, suggesting removal by scavengers or high predation on prespawners. An estimated 1928 males and 1309 females spawned in 1991, and 8021 males and 8712 females spawned in 1992. Our estimate of 3237 spawners in 1991 compared favorably to our estimate of 3520 ± 1474 prespawners staging in Lake Tahoe in mid-September. An index of kokanee abundance in Lake Tahoe has historically been based on 1-day surveys every 1 November since 1960; however, estimated total spawner abundance was 19 times higher than the annual index of 158 spawners in 1991, 141 times higher than the index count of 100 spawners in 1992. The index count and mean fork lengths of spawners (278 ± 10 mm [2 SE] for males, and 248 ± 3 mm for females) in 1991 and 1992 were the lowest on record. 相似文献
30.
Allen Clark Dotson 《Studies in History and Philosophy of Science Part B: Studies in History and Philosophy of Modern Physics》2012,43(1):64-68
Karl Popper and Herbert Dingle engaged in a fascinating debate concerning the kind of theory the special theory of relativity is. One of the issues was whether applications of the theory could be made consistent with the principle of relativity, a cornerstone of the theory itself. The principle of relativity seems to imply some sort of symmetry in results obtained for similar experiments as observed in two different inertial reference frames. Peter Hayes has recently dealt with the Dingle–Popper debate on this matter, as well as other issues. The present paper seeks to clarify what kind of symmetry is appropriate in a situation discussed by Popper, Dingle, and Hayes. 相似文献