Abstract：
:Inactivation of APC is a strongly predisposing event in the development of colorectal cancer, prompting the search for vulnerabilities specific to cells that have lost APC function. Signalling through the mTOR pathway is known to be required for epithelial cell proliferation and tumour growth, and the current paradigm suggests that a critical function of mTOR activity is to upregulate translational initiation through phosphorylation of 4EBP1 (refs 6, 7). This model predicts that the mTOR inhibitor rapamycin, which does not efficiently inhibit 4EBP1 (ref. 8), would be ineffective in limiting cancer progression in APC-deficient lesions. Here we show in mice that mTOR complex 1 (mTORC1) activity is absolutely required for the proliferation of Apc-deficient (but not wild-type) enterocytes, revealing an unexpected opportunity for therapeutic intervention. Although APC-deficient cells show the expected increases in protein synthesis, our study reveals that it is translation elongation, and not initiation, which is the rate-limiting component. Mechanistically, mTORC1-mediated inhibition of eEF2 kinase is required for the proliferation of APC-deficient cells. Importantly, treatment of established APC-deficient adenomas with rapamycin (which can target eEF2 through the mTORC1-S6K-eEF2K axis) causes tumour cells to undergo growth arrest and differentiation. Taken together, our data suggest that inhibition of translation elongation using existing, clinically approved drugs, such as the rapalogs, would provide clear therapeutic benefit for patients at high risk of developing colorectal cancer.
journal_name
Naturejournal_title
Natureauthors
Faller WJ,Jackson TJ,Knight JR,Ridgway RA,Jamieson T,Karim SA,Jones C,Radulescu S,Huels DJ,Myant KB,Dudek KM,Casey HA,Scopelliti A,Cordero JB,Vidal M,Pende M,Ryazanov AG,Sonenberg N,Meyuhas O,Hall MN,Bushell M,Wdoi
10.1038/nature13896subject
Has Abstractpub_date
2015-01-22 00:00:00pages
497-500issue
7535eissn
0028-0836issn
1476-4687journal_volume
517pub_type
杂志文章相关文献
NATURE文献大全abstract：:Locomotion relies on neural networks called central pattern generators (CPGs) that generate periodic motor commands for rhythmic movements. In vertebrates, the excitatory synaptic drive for inducing the spinal CPG can originate from either supraspinal glutamatergic inputs or from within the spinal cord. Here we identi...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/nature08323
更新日期：2009-09-17 00:00:00
abstract：:The Wnt family of secreted glycoproteins mediate cell cell interactions during cell growth and differentiation in both embryos and adults. Canonical Wnt signalling by way of the beta-catenin pathway is transduced by two receptor families. Frizzled proteins and lipoprotein-receptor-related proteins 5 and 6 (LRP5/6) bin...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/nature756
更新日期：2002-06-06 00:00:00
abstract：: ...
journal_title：Nature
pub_type： 新闻
doi：10.1038/d41586-018-07463-1
更新日期：2018-11-01 00:00:00
abstract：:The discovery of a plume of water vapour and ice particles emerging from warm fractures ('tiger stripes') in Saturn's small, icy moon Enceladus raised the question of whether the plume emerges from a subsurface liquid source or from the decomposition of ice. Previous compositional analyses of particles injected by the...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/nature10175
更新日期：2011-06-22 00:00:00
abstract：:One simple, widely accepted mechanism for generating an aberrant chromosome number, or aneuploidy, is through nondisjunction--a chromosome distribution error that occurs during mitosis when both copies of a duplicated chromosome are deposited into one daughter cell and none into the other. Shi and King challenge this ...
journal_title：Nature
pub_type： 评论,杂志文章
doi：10.1038/nature05139
更新日期：2006-08-17 00:00:00
abstract：:Living cells regulate the activity of their ion channels through a process known as gating. To open the pore, protein conformational changes must occur within a channel's membrane-spanning ion pathway. KcsA and MthK, closed and opened K(+) channels, respectively, reveal how such gating transitions occur. Pore-lining '...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/417523a
更新日期：2002-05-30 00:00:00
abstract：:The amount of energy used to run a mile is nearly the same whether it is run at top speed or at a leisurely pace (although it is used more rapidly at the higher speed). This puzzling independence of energy cost and speed is found generally among running animals, although, on a per gram basis, cost is much higher for s...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/346265a0
更新日期：1990-07-19 00:00:00
abstract：:Williams syndrome is a genetic neurodevelopmental disorder characterized by an uncommon hypersociability and a mosaic of retained and compromised linguistic and cognitive abilities. Nearly all clinically diagnosed individuals with Williams syndrome lack precisely the same set of genes, with breakpoints in chromosome b...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/nature19067
更新日期：2016-08-18 00:00:00
abstract：:Individuals with congenital or acquired prolongation of the QT interval, or long QT syndrome (LQTS), are at risk of life-threatening ventricular arrhythmia. LQTS is commonly genetic in origin but can also be caused or exacerbated by environmental factors. A missense mutation in the L-type calcium channel Ca(V)1.2 lead...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/nature09855
更新日期：2011-03-10 00:00:00
abstract：:Uridine at the first anticodon position (U34) of glutamate, lysine and glutamine transfer RNAs is universally modified by thiouridylase into 2-thiouridine (s2U34), which is crucial for precise translation by restricting codon-anticodon wobble during protein synthesis on the ribosome. However, it remains unclear how th...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/nature04896
更新日期：2006-07-27 00:00:00
abstract：:The factors determining disease severity in malaria are complex and include host polymorphisms, acquired immunity and parasite virulence. Studies in Africa have shown that severe malaria is associated with the ability of erythrocytes infected with the parasite Plasmodium falciparum to bind uninfected erythrocytes and ...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/40888
更新日期：1997-07-17 00:00:00
abstract：:More than twelve morphologically and physiologically distinct subtypes of primary somatosensory neuron report salient features of our internal and external environments1-4. It is unclear how specialized gene expression programs emerge during development to endow these subtypes with their unique properties. To assess t...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/s41586-019-1900-1
更新日期：2020-01-01 00:00:00
abstract：:T-lymphocyte co-recognition of antigen and major histocompatibility complex (MHC)-encoded molecules (such as murine Ia molecules) is thought to be mediated by a single cell-surface receptor, although the molecular mechanism by which this occurs is controversial (reviewed in ref. 1). One possibility is that the antigen...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/320176a0
更新日期：1986-03-13 00:00:00
abstract：:The annotated genomes of organisms define a 'blueprint' of their possible gene products. Post-genome analyses attempt to confirm and modify the annotation and impose a sense of the spatial, temporal and developmental usage of genetic information by the organism. Here we describe a large-scale, high-accuracy (average d...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/nature01111
更新日期：2002-10-03 00:00:00
abstract：:Unlike the electroweak sector of the standard model of particle physics, quantum chromodynamics (QCD) is surprisingly symmetric under time reversal. As there is no obvious reason for QCD being so symmetric, this phenomenon poses a theoretical problem, often referred to as the strong CP problem. The most attractive sol...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/nature20115
更新日期：2016-11-03 00:00:00
abstract：:DNA winds about itself in a right-handed or left-handed fashion at several structural levels. The double helix is generally right-handed and is given a (+) sign by convention, whereas supercoiling of the helix axis is always (-) in the cell. The winding in higher -order forms such as knots and catenanes is unknown, an...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/304559a0
更新日期：1983-08-11 00:00:00
abstract：:The recent discovery of CD4(+) T cells characterized by secretion of interleukin (IL)-17 (T(H)17 cells) and the naturally occurring regulatory FOXP3(+) CD4 T cell (nT(reg)) has had a major impact on our understanding of immune processes not readily explained by the T(H)1/T(H)2 paradigm. T(H)17 and nT(reg) cells have b...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/nature07021
更新日期：2008-07-17 00:00:00
abstract：:Transcriptional repression by nuclear receptors has been correlated to binding of the putative co-repressor, N-CoR. A complex has been identified that contains N-CoR, the Mad presumptive co-repressor mSin3, and the histone deacetylase mRPD3, and which is required for both nuclear receptor- and Mad-dependent repression...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/387043a0
更新日期：1997-05-01 00:00:00
abstract：:The immunophilins cyclophilin and FK506 binding protein (FKBP) are small, predominantly soluble proteins that bind the immunosuppressant drugs cyclosporin A and FK506, respectively, with high affinity, and which seem to mediate their pharmacological actions. The Ca(2+)-dependent protein phosphatase, calcineurin, binds...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/358584a0
更新日期：1992-08-13 00:00:00
abstract：:Distrust in scientific expertise1-14 is dangerous. Opposition to vaccination with a future vaccine against SARS-CoV-2, the causal agent of COVID-19, for example, could amplify outbreaks2-4, as happened for measles in 20195,6. Homemade remedies7,8 and falsehoods are being shared widely on the Internet, as well as dismi...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/s41586-020-2281-1
更新日期：2020-06-01 00:00:00
abstract：:Epidermal growth factor (EGF) and transforming growth factor type I (TGF) are polypeptides of 53 and 50 amino acid residues, respectively. Both bind to EGF receptor, a 1,200-residue transmembranous glycoprotein, leading to phosphorylation of the receptor, enhancement of its tyrosine-specific kinase activity and ultima...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/313491a0
更新日期：1985-02-07 00:00:00
abstract：:Recombination is the exchange of information between two homologous chromosomes during meiosis. The rate of recombination per nucleotide, which profoundly affects the evolution of chromosomal segments, is calculated by comparing genetic and physical maps. Human physical maps have been constructed using cytogenetics, o...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/35057185
更新日期：2001-02-15 00:00:00
abstract：:Occupancy of the T-cell antigen receptor is insufficient to induce T-cell activation optimally; a second co-stimulatory signal is required. Exposure of T-cell clones to complexes of antigen with major histocompatibility complex molecules in the absence of the co-stimulatory signal induces a state of clonal anergy. Thi...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/356607a0
更新日期：1992-04-16 00:00:00
abstract：:T-cell lines established from individuals infected with human T-cell leukaemia virus (HTLV) or generated by co-cultivation of normal human T cells with HTLV-infected T-cells, express class II (HLA-D/DR or Ia) antigens of the major histocompatibility complex (MHC) and interleukin-2 (IL-2) receptors. Because the express...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/312275a0
更新日期：1984-11-15 00:00:00
abstract：:Lignin is a complex polymer of phenylpropanoid subunits. It is an essential component of woody tissue, to which it imparts structural rigidity. Lignin is remarkably resistant to degradation by most microbes; nevertheless, a few species of white-rot fungi are able to catalyse its oxidation to CO2. Its biodegradation is...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/326520a0
更新日期：1987-04-02 00:00:00
abstract：:The rapid development of the silk glands of Bombyx mori during the last larval instar shows two phases. During the first 4 days, in both the middle and posterior parts of the silk glands, the ribosomal machinery is assembled and the synthesis of housekeeping proteins starts. During the second phase (the last 4 days), ...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/290267a0
更新日期：1981-03-19 00:00:00
abstract：:Adsorption-based phenomena are important in gas separations, such as the treatment of greenhouse-gas and toxic-gas pollutants, and in water-adsorption-based heat pumps for solar cooling systems. The ability to tune the pore size, shape and functionality of crystalline porous coordination polymers--or metal-organic fra...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/nature17430
更新日期：2016-04-21 00:00:00
abstract：:When present in single-stranded DNA, palindromic or quasi-palindromic sequences have the potential to form complex secondary structures, including hairpins, which may facilitate interstrand misalignment of direct repeats and be responsible for diverse types of replication-based mutations, including deletions, addition...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/352544a0
更新日期：1991-08-08 00:00:00
abstract：:Many homeobox genes are clustered in a linear array along a chromosome, reflecting their ordered expression along the anterior-posterior axis of the embryo. Expression patterns as well as grafting, ectopic expression and loss-of-function experiments suggest that the Hox genes encode a combinatorial system of positiona...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/368747a0
更新日期：1994-04-21 00:00:00
abstract：:Seafloor spreading is largely unobserved because 98 per cent of the global mid-ocean-ridge system is below the ocean surface. Our understanding of the dynamic processes that control seafloor spreading is thus inferred largely from geophysical observations of spreading events on land at Afar in East Africa and Iceland....
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/nature20116
更新日期：2016-12-08 00:00:00
