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排序方式: 共有213条查询结果,搜索用时 15 毫秒
71.
72.
Raj L Ide T Gurkar AU Foley M Schenone M Li X Tolliday NJ Golub TR Carr SA Shamji AF Stern AM Mandinova A Schreiber SL Lee SW 《Nature》2011,475(7355):231-234
Malignant transformation, driven by gain-of-function mutations in oncogenes and loss-of-function mutations in tumour suppressor genes, results in cell deregulation that is frequently associated with enhanced cellular stress (for example, oxidative, replicative, metabolic and proteotoxic stress, and DNA damage). Adaptation to this stress phenotype is required for cancer cells to survive, and consequently cancer cells may become dependent upon non-oncogenes that do not ordinarily perform such a vital function in normal cells. Thus, targeting these non-oncogene dependencies in the context of a transformed genotype may result in a synthetic lethal interaction and the selective death of cancer cells. Here we used a cell-based small-molecule screening and quantitative proteomics approach that resulted in the unbiased identification of a small molecule that selectively kills cancer cells but not normal cells. Piperlongumine increases the level of reactive oxygen species (ROS) and apoptotic cell death in both cancer cells and normal cells engineered to have a cancer genotype, irrespective of p53 status, but it has little effect on either rapidly or slowly dividing primary normal cells. Significant antitumour effects are observed in piperlongumine-treated mouse xenograft tumour models, with no apparent toxicity in normal mice. Moreover, piperlongumine potently inhibits the growth of spontaneously formed malignant breast tumours and their associated metastases in mice. Our results demonstrate the ability of a small molecule to induce apoptosis selectively in cells that have a cancer genotype, by targeting a non-oncogene co-dependency acquired through the expression of the cancer genotype in response to transformation-induced oxidative stress. 相似文献
73.
Eukaryotic messenger RNAs contain a modified guanosine, termed a cap, at their 5' ends. Translation of mRNAs requires the binding of an initiation factor, eIF4E, to the cap structure. Here, we describe a family of proteins that through a shared sequence regulate cap-dependent translation. The biological importance of this translational regulation is immense, and affects such processes as cell growth, development, oncogenic transformation and perhaps even axon pathfinding and memory consolidation. 相似文献
74.
Galarneau G Palmer CD Sankaran VG Orkin SH Hirschhorn JN Lettre G 《Nature genetics》2010,42(12):1049-1051
We used resequencing and genotyping in African Americans with sickle cell anemia (SCA) to characterize associations with fetal hemoglobin (HbF) levels at the BCL11A, HBS1L-MYB and β-globin loci. Fine-mapping of HbF association signals at these loci confirmed seven SNPs with independent effects and increased the explained heritable variation in HbF levels from 38.6% to 49.5%. We also identified rare missense variants that causally implicate MYB in HbF production. 相似文献
75.
Lesport E Baudhuin J Sousa S LeMaoult J Zamborlini A Rouas-Freiss N Carosella ED Favier B 《Cellular and molecular life sciences : CMLS》2011,68(20):3385-3399
Vγ9Vδ2 T cells play a crucial role in the antitumoral immune response through cytokine production and cytotoxicity. Although
the expression of the immunomodulatory molecule HLA-G has been found in diverse tumors, its impact on Vγ9Vδ2 T-cell functions
remains unknown. Here we showed that soluble HLA-G inhibits Vγ9Vδ2 T-cell proliferation without inducing apoptosis. Moreover,
soluble HLA-G inhibited the Vγ9Vδ2 T-cell production of IFN-γ induced by phosphoantigen stimulation. The reduction in Vγ9Vδ2
T-cell IFN-γ production was also induced by membrane-bound or soluble HLA-G expressed by tumor cell lines. Finally, primary
tumor cells inhibited Vγ9Vδ2 T-cell proliferation and IFN-γ production through HLA-G. In this context, HLA-G impaired Vγ9Vδ2
T-cell cytotoxicity by interacting with ILT2 inhibitory receptor. These data demonstrate that HLA-G inhibits the anti-tumoral
functions of Vγ9Vδ2 T cells and imply that treatments targeting HLA-G could optimize Vγ9Vδ2 T-cell-mediated immunotherapy
of cancer. 相似文献
76.
Carosella ED Gregori S Rouas-Freiss N LeMaoult J Menier C Favier B 《Cellular and molecular life sciences : CMLS》2011,68(3):353-368
The non-classical HLA class I molecule HLA-G was initially shown to play a major role in feto–maternal tolerance. Since this
discovery, it has been established that HLA-G is a tolerogenic molecule which participates to the control of the immune response.
In this review, we summarize the recent advances on (1) the multiple structures of HLA-G, which are closely associated with
their role in the inhibition of NK cell cytotoxicity, (2) the factors that regulate the expression of HLA-G and its receptors,
(3) the mechanism of action of HLA-G at the immunological synapse and through trogocytosis, and (4) the generation of suppressive
cells through HLA-G. Moreover, we also review recent findings on the non-immunological functions of HLA-G in erythropoiesis
and angiogenesis. 相似文献
77.
In amniotes, all of the tissues of the adult arise from the epiblast, one of the two layers of cells present in the early embryo; the mesoderm and gut endoderm arise from an epiblast-derived structure known as the primitive streak. The monoclonal antibody HNK-1 recognizes the cells of the primitive streak in the chick embryo. Before streak formation, HNK-1 identifies cells that are randomly distributed within the epiblast. We have now used two novel ways to study cell lineage and commitment to show that the epiblast of the early chick embryo contains two distinct populations of cells with different developmental fates at a stage during which 'mesodermal induction' is believed to occur. One cell population, recognized by monoclonal antibody HNK-1, is destined to form mesoderm and endoderm; the rest of the epiblast is unable to give rise to mesoderm if this population of cells is removed. 相似文献
78.
79.
The fractional quantum Hall effect, where plateaus in the Hall resistance at values of h/nue2 coexist with zeros in the longitudinal resistance, results from electron correlations in two dimensions under a strong magnetic field. (Here h is Planck's constant, nu the filling factor and e the electron charge.) Current flows along the sample edges and is carried by charged excitations (quasiparticles) whose charge is a fraction of the electron charge. Although earlier research concentrated on odd denominator fractional values of nu, the observation of the even denominator nu = 5/2 state sparked much interest. This state is conjectured to be characterized by quasiparticles of charge e/4, whose statistics are 'non-abelian'-in other words, interchanging two quasiparticles may modify the state of the system into a different one, rather than just adding a phase as is the case for fermions or bosons. As such, these quasiparticles may be useful for the construction of a topological quantum computer. Here we report data on shot noise generated by partitioning edge currents in the nu = 5/2 state, consistent with the charge of the quasiparticle being e/4, and inconsistent with other possible values, such as e/2 and e. Although this finding does not prove the non-abelian nature of the nu = 5/2 state, it is the first step towards a full understanding of these new fractional charges. 相似文献
80.