Abstract:
:The Fbw7 (F-box/WD repeat-containing protein 7) ubiquitin ligase targets multiple oncoproteins for degradation and is commonly mutated in cancers. Like other pleiotropic tumor suppressors, Fbw7's complex biology has impeded our understanding of how Fbw7 mutations promote tumorigenesis and hindered the development of targeted therapies. To address these needs, we employed a transfer learning approach to derive gene-expression signatures from The Cancer Gene Atlas datasets that predict Fbw7 mutational status across tumor types and identified the pathways enriched within these signatures. Genes involved in mitochondrial function were highly enriched in pan-cancer signatures that predict Fbw7 mutations. Studies in isogenic colorectal cancer cell lines that differed in Fbw7 mutational status confirmed that Fbw7 mutations increase mitochondrial gene expression. Surprisingly, Fbw7 mutations shifted cellular metabolism toward oxidative phosphorylation and caused context-specific metabolic vulnerabilities. Our approach revealed unexpected metabolic reprogramming and possible therapeutic targets in Fbw7-mutant cancers and provides a framework to study other complex, oncogenic mutations.
journal_name
Proc Natl Acad Sci U S Aauthors
Davis RJ,Gönen M,Margineantu DH,Handeli S,Swanger J,Hoellerbauer P,Paddison PJ,Gu H,Raftery D,Grim JE,Hockenbery DM,Margolin AA,Clurman BEdoi
10.1073/pnas.1718338115subject
Has Abstractpub_date
2018-05-22 00:00:00pages
5462-5467issue
21eissn
0027-8424issn
1091-6490pii
1718338115journal_volume
115pub_type
杂志文章abstract::The goal of this study was to characterize and classify pulmonary neuroendocrine tumors based on array comparative genomic hybridization (aCGH). Using aCGH, we performed karyotype analysis of 33 small cell lung cancer (SCLC) tumors, 13 SCLC cell lines, 19 bronchial carcinoids, and 9 gastrointestinal carcinoids. In con...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1008132107
更新日期:2010-07-20 00:00:00
abstract::One hundred fifty years ago glial cells were discovered as a second, non-neuronal, cell type in the central nervous system. To ascribe a function to these new, enigmatic cells, it was suggested that they either glue the neurons together (the Greek word "gammalambdaiotaalpha" means "glue") or provide a robust scaffold ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0606150103
更新日期:2006-11-21 00:00:00
abstract::The neighbor-exclusion principle is one of the most general and interesting rules describing intercalative DNA binding by small molecules. It suggests that such binding can only occur at every other base-pair site, reflecting a very large negative cooperativity in the binding process. We have carried out molecular mec...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.84.16.5735
更新日期:1987-08-01 00:00:00
abstract::Interleukin 2 (IL-2) receptors on activated T cells exist in high- and low-affinity configurations, both of which share a ligand-binding component known as the Tac protein. Although almost all binding of IL-2 to such cells was inhibited by an antibody to Tac, the predominant component of binding on the natural killer ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.84.7.2002
更新日期:1987-04-01 00:00:00
abstract::Zooxanthellae are unicellular algae that occur as endosymbionts in many hundreds of common marine invertebrates. The issue of zooxanthella diversity has been difficult to address. Most zooxanthellae have been placed in the dinoflagellate genus Symbiodinium as one or several species that are not easily distinguished. W...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.89.8.3639
更新日期:1992-04-15 00:00:00
abstract::Operant conditioning techniques were used to assess how gender and song familiarity affect song discrimination in adult zebra finches (Taeniopygia guttata). Twenty-five males and females, divided into five cohorts, were trained to discriminate between conspecific songs at different times of year. Males discriminating ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.89.4.1368
更新日期:1992-02-15 00:00:00
abstract::The 24 nucleotides comprising the carbohydrate-recognition domain of Maackia amurensis hemagglutinin (MAH) cDNA were randomly mutated. The mutant lectins were expressed as glutathione-S-transferase fusion proteins in Escherichia coli and 16 clones were randomly chosen. Although all of 16 recombinant lectins reacted st...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.041621998
更新日期:2001-02-27 00:00:00
abstract::Cellular and molecular signals involved in axon elongation versus collateral and arbor formation may be intrinsic to developing neurons, or they may derive from targets. To identify signals regulating axon growth modes, we have developed a culture system in which trigeminal ganglion cells are challenged by various tar...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.90.15.7235
更新日期:1993-08-01 00:00:00
abstract::It is shown that, under certain standard assumptions, such as extended Riemann hypotheses, the scattering matrix varphi(s) for generic Gamma = SL(2, R) is unexpectedly of order 2. This leads to the conjecture that the generic cofinite Gamma has very few Maass cusp forms. ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.82.11.3533
更新日期:1985-06-01 00:00:00
abstract::Protein acetylation, especially histone acetylation, is the subject of both research and clinical investigation. At least four small-molecule histone deacetylase inhibitors are currently in clinical trials for the treatment of cancer. These and other inhibitors also affect microtubule acetylation. A multidimensional, ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0430973100
更新日期:2003-04-15 00:00:00
abstract::Fungi that are resistant or sensitive to the singlet oxygen-generating toxin cercosporin were assayed for their ability to detoxify it by reduction. Cercosporin reduction was assayed microscopically by using bandpass filters to differentiate between fluorescence emission from cercosporin and reduced cercosporin. Hypha...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.89.20.9588
更新日期:1992-10-15 00:00:00
abstract::A lysine-to-arginine substitution at amino acid 65 (K65R) in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) is associated with resistance to 2',3'-dideoxycytidine (ddC), 2',3'-dideoxyinosine (ddI), and the (-) enantiomer of 2',3'-dideoxy-3'-thiacytidine (3TC). To further characterize the molecu...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.92.7.2760
更新日期:1995-03-28 00:00:00
abstract::The energetics of the TiO(2) polymorphs (rutile, anatase, and brookite) were studied by high temperature oxide melt drop solution calorimetry. Relative to bulk rutile, bulk brookite is 0.71 +/- 0.38 kJ/mol (6) and bulk anatase is 2.61 +/- 0.41 kJ/mol higher in enthalpy. The surface enthalpies of rutile, brookite, and ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.251534898
更新日期:2002-04-30 00:00:00
abstract::Radiation therapy is a widely used cancer treatment, but it causes side effects even when localized radiotherapy is used. Extensive apoptosis of microvascular endothelial cells of the lamina propria is the primary lesion initiating intestinal radiation damage after abdominal radiation therapy. Many in vitro studies su...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0307575101
更新日期:2004-04-13 00:00:00
abstract::Induced seismicity linked to geothermal resource exploitation, hydraulic fracturing, and wastewater disposal is evolving into a global issue because of the increasing energy demand. Moderate to large induced earthquakes, causing widespread hazards, are often related to fluid injection into deep permeable formations th...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1819225116
更新日期:2019-08-13 00:00:00
abstract::We previously demonstrated that platelets express high levels of the tyrosine protein kinase pp60c-src. By a quantitative immunoblot assay, it is shown in this report that pp60c-src represents 0.2-0.4% of total platelet protein. The expression of high levels of pp60c-src in platelets correlated with high levels of tot...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.86.3.901
更新日期:1989-02-01 00:00:00
abstract::Although major research efforts have focused on how specific components of foodstuffs affect health, relatively little is known about a more fundamental aspect of diet, the frequency and circadian timing of meals, and potential benefits of intermittent periods with no or very low energy intakes. The most common eating...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1413965111
更新日期:2014-11-25 00:00:00
abstract::Many important hominid-bearing fossil localities in East Africa are in regions that are extremely hot and dry. Although humans are well adapted to such conditions, it has been inferred that East African environments were cooler or more wooded during the Pliocene and Pleistocene when this region was a central stage of ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1001824107
更新日期:2010-06-22 00:00:00
abstract::The natural history of follicular lymphoma (FL) is frequently characterized by transformation to a more aggressive diffuse large B cell lymphoma (DLBCL). We compared the gene-expression profiles between transformed DLBCL and their antecedent FL. No genes were observed to increase or decrease their expression in all of...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.132253599
更新日期:2002-06-25 00:00:00
abstract::Secretion of inflammatory mediators by rat mast cells (line RBL-2H3) was earlier shown to be inhibited upon clustering a membrane glycoprotein by monoclonal antibody G63. This glycoprotein, named mast cell function-associated antigen (MAFA), was also shown to interfere with the coupling cascade of the type 1 Fc epsilo...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.92.20.9397
更新日期:1995-09-26 00:00:00
abstract::When G-protein alpha subunits binds GTP and Mg(2+), they transition from their inactive to their active conformation. This transition is accompanied by completion of the coordination shell of Mg(2+) with electrons from six oxygens: two water molecules, the ss and gamma phosphoryls of GTP, a helix-alpha1 Ser, and a swi...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1004803107
更新日期:2010-05-25 00:00:00
abstract::The PsaF-deficient mutant 3bF of Chlamydomonas reinhardtii was used to modify PsaF by nuclear transformation and site-directed mutagenesis. Four lysine residues in the N-terminal domain of PsaF, which have been postulated to form the positively charged face of a putative amphipathic alpha-helical structure were altere...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.95.13.7339
更新日期:1998-06-23 00:00:00
abstract::Cyclophilins are a family of ubiquitous proteins that are the intracellular target of the immunosuppressant drug cyclosporin A. Although cyclophilins catalyze peptidylprolyl cis-trans isomerization in vitro, it has remained open whether they also perform this function in vivo. Here we show that Cpr3p, a cyclophilin in...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.92.14.6319
更新日期:1995-07-03 00:00:00
abstract::T cell activation and tolerance are regulated by costimulatory molecules. Although PD-1 serves as a crucial negative regulator of T cells, the function of its ligands, PDL1 and PDL2, is still controversial. In this study, we created a PDL2-deficient mouse to characterize its function in T cell activation and tolerance...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0601347103
更新日期:2006-08-01 00:00:00
abstract::The anticonvulsants phenytoin and carbamazepine interact allosterically with the batrachotoxin binding site of sodium channels. In the present study, we demonstrate an autoradiographic technique to localize the batrachotoxin binding site on sodium channels in rat brain using [3H]batrachotoxinin-A 20-alpha-benzoate (BT...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.84.9.3051
更新日期:1987-05-01 00:00:00
abstract::An interpretation is given of recent experiments by Brunori et al. on the binding of carbon monoxide by hemoglobin under photodissociating conditions. It is shown that their results follow directly from scalable models for hemoglobin in which the protein-modulated interactions are separable from the ligand binding. ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.70.3.673
更新日期:1973-03-01 00:00:00
abstract::Hybrid wheat plants are superior in yield and growth characteristics compared with their homozygous parents. The commercial production of wheat hybrids is difficult because of the inbreeding nature of wheat and the lack of a practical fertility control that enforces outcrossing. We describe a hybrid wheat system that ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1402836111
更新日期:2014-06-24 00:00:00
abstract::We have studied the effect of the cholinergic agonist carbachol on the spontaneous release of glutamate in cultured rat hippocampal cells. Spontaneous excitatory postsynaptic currents (sEPSCs) through glutamatergic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type channels were recorded by means of ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.94.22.12224
更新日期:1997-10-28 00:00:00
abstract::Bacteriophage T3-induced RNA polymerase, upon copying its specific template, native T3 DNA, initiates RNA chains only with GTP. Denaturation of the DNA results in loss of template specificity for the polymerase. With denatured T3 DNA as template, T3 polymerase initiates RNA chains with both ATP and GTP, and the averag...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.69.1.55
更新日期:1972-01-01 00:00:00
abstract::Given the known neuroreparative actions of IL-33 in experimental models of central nervous system (CNS) injury, we predicted that compounds which induce IL-33 are likely to promote remyelination. We found anacardic acid as a candidate molecule to serve as a therapeutic agent to promote remyelination. Addition of anaca...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.2006566117
更新日期:2020-09-01 00:00:00