DHODH modulates transcriptional elongation in the neural crest and melanoma.

Abstract:

:Melanoma is a tumour of transformed melanocytes, which are originally derived from the embryonic neural crest. It is unknown to what extent the programs that regulate neural crest development interact with mutations in the BRAF oncogene, which is the most commonly mutated gene in human melanoma. We have used zebrafish embryos to identify the initiating transcriptional events that occur on activation of human BRAF(V600E) (which encodes an amino acid substitution mutant of BRAF) in the neural crest lineage. Zebrafish embryos that are transgenic for mitfa:BRAF(V600E) and lack p53 (also known as tp53) have a gene signature that is enriched for markers of multipotent neural crest cells, and neural crest progenitors from these embryos fail to terminally differentiate. To determine whether these early transcriptional events are important for melanoma pathogenesis, we performed a chemical genetic screen to identify small-molecule suppressors of the neural crest lineage, which were then tested for their effects on melanoma. One class of compound, inhibitors of dihydroorotate dehydrogenase (DHODH), for example leflunomide, led to an almost complete abrogation of neural crest development in zebrafish and to a reduction in the self-renewal of mammalian neural crest stem cells. Leflunomide exerts these effects by inhibiting the transcriptional elongation of genes that are required for neural crest development and melanoma growth. When used alone or in combination with a specific inhibitor of the BRAF(V600E) oncogene, DHODH inhibition led to a marked decrease in melanoma growth both in vitro and in mouse xenograft studies. Taken together, these studies highlight developmental pathways in neural crest cells that have a direct bearing on melanoma formation.

journal_name

Nature

journal_title

Nature

authors

White RM,Cech J,Ratanasirintrawoot S,Lin CY,Rahl PB,Burke CJ,Langdon E,Tomlinson ML,Mosher J,Kaufman C,Chen F,Long HK,Kramer M,Datta S,Neuberg D,Granter S,Young RA,Morrison S,Wheeler GN,Zon LI

doi

10.1038/nature09882

subject

Has Abstract

pub_date

2011-03-24 00:00:00

pages

518-22

issue

7339

eissn

0028-0836

issn

1476-4687

pii

nature09882

journal_volume

471

pub_type

杂志文章

相关文献

NATURE文献大全
  • An unexpectedly rapid decline in the X-ray afterglow emission of long gamma-ray bursts.

    abstract::'Long' gamma-ray bursts (GRBs) are commonly accepted to originate in the explosion of particularly massive stars, which give rise to highly relativistic jets. Inhomogeneities in the expanding flow result in internal shock waves that are believed to produce the gamma-rays we see. As the jet travels further outward into...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature03934

    authors: Tagliaferri G,Goad M,Chincarini G,Moretti A,Campana S,Burrows DN,Perri M,Barthelmy SD,Gehrels N,Krimm H,Sakamoto T,Kumar P,Mészáros PI,Kobayashi S,Zhang B,Angelini L,Banat P,Beardmore AP,Capalbi M,Covino S,Cusuman

    更新日期:2005-08-18 00:00:00

  • Reassembly of shattered chromosomes in Deinococcus radiodurans.

    abstract::Dehydration or desiccation is one of the most frequent and severe challenges to living cells. The bacterium Deinococcus radiodurans is the best known extremophile among the few organisms that can survive extremely high exposures to desiccation and ionizing radiation, which shatter its genome into hundreds of short DNA...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature05160

    authors: Zahradka K,Slade D,Bailone A,Sommer S,Averbeck D,Petranovic M,Lindner AB,Radman M

    更新日期:2006-10-05 00:00:00

  • A natural variant and engineered mutation in a GPCR promote DEET resistance in C. elegans.

    abstract::DEET (N,N-diethyl-meta-toluamide) is a synthetic chemical identified by the US Department of Agriculture in 1946 in a screen for repellents to protect soldiers from mosquito-borne diseases1,2. Since its discovery, DEET has become the world's most widely used arthropod repellent and is effective against invertebrates s...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/s41586-018-0546-8

    authors: Dennis EJ,Dobosiewicz M,Jin X,Duvall LB,Hartman PS,Bargmann CI,Vosshall LB

    更新日期:2018-10-01 00:00:00

  • Female mating bias results in conflicting sex-specific offspring fitness.

    abstract::Indirect-benefit models of sexual selection assert that females gain heritable offspring advantages through a mating bias for males of superior genetic quality. This has generally been tested by associating a simple morphological quality indicator (for example, bird tail length) with offspring viability. However, sele...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature02492

    authors: Fedorka KM,Mousseau TA

    更新日期:2004-05-06 00:00:00

  • Modulation of hydrophobic interactions by proximally immobilized ions.

    abstract::The structure of water near non-polar molecular fragments or surfaces mediates the hydrophobic interactions that underlie a broad range of interfacial, colloidal and biophysical phenomena. Substantial progress over the past decade has improved our understanding of hydrophobic interactions in simple model systems, but ...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature14018

    authors: Ma CD,Wang C,Acevedo-Vélez C,Gellman SH,Abbott NL

    更新日期:2015-01-15 00:00:00

  • Carbon isotope composition of individual amino acids in the Murchison meteorite.

    abstract::A significant portion of prebiotic organic matter on the early Earth may have been introduced by carbonaceous asteroids and comets. The distribution and stable-isotope composition of individual organic compounds in carbonaceous meteorites, which are thought to be derived from asteroidal parent bodies, may therefore pr...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/348047a0

    authors: Engel MH,Macko SA,Silfer JA

    更新日期:1990-11-01 00:00:00

  • Directional guidance of neuronal migration in the olfactory system by the protein Slit.

    abstract::Although cell migration is crucial for neural development, molecular mechanisms guiding neuronal migration have remained unclear. Here we report that the secreted protein Slit repels neuronal precursors migrating from the anterior subventricular zone in the telencephalon to the olfactory bulb. Our results provide a di...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/22477

    authors: Wu W,Wong K,Chen J,Jiang Z,Dupuis S,Wu JY,Rao Y

    更新日期:1999-07-22 00:00:00

  • Inhibition of climbing fibres is a signal for the extinction of conditioned eyelid responses.

    abstract::A fundamental tenet of cerebellar learning theories asserts that climbing fibre afferents from the inferior olive provide a teaching signal that promotes the gradual adaptation of movements. Data from several forms of motor learning provide support for this tenet. In pavlovian eyelid conditioning, for example, where a...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/416330a

    authors: Medina JF,Nores WL,Mauk MD

    更新日期:2002-03-21 00:00:00

  • Molecular basis of seasonal time measurement in Arabidopsis.

    abstract::Several organisms have evolved the ability to measure daylength, or photoperiod, allowing them to adjust their development in anticipation of annual seasonal changes. Daylength measurement requires the integration of temporal information, provided by the circadian system, with light/dark discrimination, initiated by s...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature00996

    authors: Yanovsky MJ,Kay SA

    更新日期:2002-09-19 00:00:00

  • Antibody-dependent cell-mediated antibacterial activity of intestinal lymphocytes with secretory IgA.

    abstract::Secretory antibodies of the IgA class (sIgA) are thought to have an important role in the defence against bacteria at mucosal surfaces--the level at which the infectious agents first come into contact with the host. However, the mechanism by which sIgA exert their antibacterial activity is still a matter of debate. Af...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/306184a0

    authors: Tagliabue A,Nencioni L,Villa L,Keren DF,Lowell GH,Boraschi D

    更新日期:1983-11-10 00:00:00

  • Non-classical correlations between single photons and phonons from a mechanical oscillator.

    abstract::Interfacing a single photon with another quantum system is a key capability in modern quantum information science. It allows quantum states of matter, such as spin states of atoms, atomic ensembles or solids, to be prepared and manipulated by photon counting and, in particular, to be distributed over long distances. S...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature16536

    authors: Riedinger R,Hong S,Norte RA,Slater JA,Shang J,Krause AG,Anant V,Aspelmeyer M,Gröblacher S

    更新日期:2016-02-18 00:00:00

  • Computational comparison of two draft sequences of the human genome.

    abstract::We are in the enviable position of having two distinct drafts of the human genome sequence. Although gaps, errors, redundancy and incomplete annotation mean that individually each falls short of the ideal, many of these problems can be assessed by comparison. Here we present some comparative analyses of these drafts. ...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/35057055

    authors: Aach J,Bulyk ML,Church GM,Comander J,Derti A,Shendure J

    更新日期:2001-02-15 00:00:00

  • Dogfish hair cells sense hydrostatic pressure.

    abstract::Many marine invertebrates and fish respond to hydrostatic pressure in order to regulate their depth and synchronize their behaviour to tidal cycles. Here we investigate the effect of hydrostatic pressure on the vestibular hair cells located in the labyrinth of the dogfish Scyliorhinus canicula, and find that it modula...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/415495a

    authors: Fraser PJ,Shelmerdine RL

    更新日期:2002-01-31 00:00:00

  • Mechanism of arginine sensing by CASTOR1 upstream of mTORC1.

    abstract::The mechanistic Target of Rapamycin Complex 1 (mTORC1) is a major regulator of eukaryotic growth that coordinates anabolic and catabolic cellular processes with inputs such as growth factors and nutrients, including amino acids. In mammals arginine is particularly important, promoting diverse physiological effects suc...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature19079

    authors: Saxton RA,Chantranupong L,Knockenhauer KE,Schwartz TU,Sabatini DM

    更新日期:2016-08-11 00:00:00

  • Sharply increased mass loss from glaciers and ice caps in the Canadian Arctic Archipelago.

    abstract::Mountain glaciers and ice caps are contributing significantly to present rates of sea level rise and will continue to do so over the next century and beyond. The Canadian Arctic Archipelago, located off the northwestern shore of Greenland, contains one-third of the global volume of land ice outside the ice sheets, but...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature10089

    authors: Gardner AS,Moholdt G,Wouters B,Wolken GJ,Burgess DO,Sharp MJ,Cogley JG,Braun C,Labine C

    更新日期:2011-05-19 00:00:00

  • Helical self-assembled polymers from cooperative stacking of hydrogen-bonded pairs.

    abstract::The double helix of DNA epitomizes this molecule's ability to self-assemble in aqueous solutions into a complex chiral structure using hydrogen bonding and hydrophobic interactions. Non-covalently interacting molecules in organic solvents are used to design systems that similarly form controlled architectures. Periphe...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/35025027

    authors: Hirschberg JH,Brunsveld L,Ramzi A,Vekemans JA,Sijbesma RP,Meijer EW

    更新日期:2000-09-14 00:00:00

  • Seizure-related brain damage induced by cholinergic agents.

    abstract::Distinctive acute brain damage involving limbic and related brain regions develops in adult rats following sustained limbic seizures induced by systemic administration of kainic acid or dipiperidinoethane (DPE) or by intra-amygdaloid injection of kainic acid or folic acid. This seizure-brain damage (S-BD) syndrome is ...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/301520a0

    authors: Olney JW,de Gubareff T,Labruyere J

    更新日期:1983-02-10 00:00:00

  • Amide-directed photoredox-catalysed C-C bond formation at unactivated sp3 C-H bonds.

    abstract::Carbon-carbon (C-C) bond formation is paramount in the synthesis of biologically relevant molecules, modern synthetic materials and commodity chemicals such as fuels and lubricants. Traditionally, the presence of a functional group is required at the site of C-C bond formation. Strategies that allow C-C bond formation...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature19810

    authors: Chu JC,Rovis T

    更新日期:2016-11-10 00:00:00

  • Gravitationally redshifted absorption lines in the X-ray burst spectra of a neutron star.

    abstract::The fundamental properties of neutron stars provide a direct test of the equation of state of cold nuclear matter, a relationship between pressure and density that is determined by the physics of the strong interactions between the particles that constitute the star. The most straightforward method of determining thes...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature01159

    authors: Cottam J,Paerels F,Mendez M

    更新日期:2002-11-07 00:00:00

  • Fossil mammals and artefacts from the Middle Awash Valley, Ethiopia.

    abstract::A review of fossil mammalian faunas from the Middle Awash indicates they span most of the later Neogene and document evolutionary change in several mammalian groups, especially Primates, Proboscidea and Artiodactyla. Oldowan artefacts first appear in the late Pliocene, while Acheulian and later industries and apparent...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/298025a0

    authors: Kalb JE,Jolly CJ,Mebrate A,Tebedge S,Smart C,Oswald EB,Cramer D,Whitehead P,Wood CB,Conroy GC,Adefris T,Sperling L,Kana B

    更新日期:1982-07-01 00:00:00

  • Anaerobic microbial metabolism can proceed close to thermodynamic limits.

    abstract::Many fermentative bacteria obtain energy for growth by reactions in which the change in free energy (DeltaG') is less than that needed to synthesize ATP. These bacteria couple substrate metabolism directly to ATP synthesis, however, by classical phosphoryl transfer reactions. An explanation for the energy economy of t...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/415454a

    authors: Jackson BE,McInerney MJ

    更新日期:2002-01-24 00:00:00

  • Juggling research and family life: honest reflections from scientist dads.

    abstract:: ...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/d41586-018-07511-w

    authors: Payne D

    更新日期:2018-11-01 00:00:00

  • A role for branchpoints in splicing in vivo.

    abstract::The nucleotides immediately surrounding intron/exon junctions of genes transcribed by RNA polymerase B can be derived from 'consensus' sequences for donor and acceptor splice sites by only a few base changes. Studies in vivo have underlined the importance of these junction nucleotides for splicing. In higher eukaryote...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/315430a0

    authors: Rautmann G,Breathnach R

    更新日期:1985-05-30 00:00:00

  • Lack of linkage of familial Wilms' tumour to chromosomal band 11p13.

    abstract::Wilms' tumour (WT), a paediatric renal neoplasm, affect approximately 1 in 10,000 children. One or both kidneys can be affected and 5-10% of tumours are bilateral. Most tumours occur sporadically; however, around 1% of the cases are familial, with siblings or cousins most often being affected. Familial cases are more ...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/336377a0

    authors: Huff V,Compton DA,Chao LY,Strong LC,Geiser CF,Saunders GF

    更新日期:1988-11-24 00:00:00

  • Enhancement of T-cell responsiveness by the lymphocyte-specific tyrosine protein kinase p56lck.

    abstract::Lymphocyte-specific tyrosine protein kinase p56lck is physically associated with CD4 and CD8 T-cell surface molecules, suggesting that it may transduce CD4/CD8-triggered tyrosine phosphorylation signals during antigen stimulation. Indeed, antibody-mediated aggregation of CD4 (to mimic interaction with its ligand, majo...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/350062a0

    authors: Abraham N,Miceli MC,Parnes JR,Veillette A

    更新日期:1991-03-07 00:00:00

  • Orbital Kondo effect in carbon nanotubes.

    abstract::Progress in the fabrication of nanometre-scale electronic devices is opening new opportunities to uncover deeper aspects of the Kondo effect--a characteristic phenomenon in the physics of strongly correlated electrons. Artificial single-impurity Kondo systems have been realized in various nanostructures, including sem...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature03422

    authors: Jarillo-Herrero P,Kong J,van der Zant HS,Dekker C,Kouwenhoven LP,De Franceschi S

    更新日期:2005-03-24 00:00:00

  • Single channel recordings of K+ currents in squid axons.

    abstract::Ionic currents from individual K+ channels in squid axon membrane have been recorded. At hyperpolarizing membrane voltages, unit events occur as widely spaced rectangular pulses with short interruptions. The frequency of occurrence of the units increases strongly when the membrane is depolarized. ...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/285140a0

    authors: Conti F,Neher E

    更新日期:1980-05-15 00:00:00

  • Models for metal ion function in carbonic anhydrase.

    abstract::A model catalyst is described which has properties in common with carbonic anhydrase. The model demonstrates the availability of a mechanism, previously only hypothetical, for the action of the enzyme. It also shows, however, that this mechanism alone is not adequate to produce the high activity of the enzyme. ...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/258677a0

    authors: Woolley P

    更新日期:1975-12-25 00:00:00

  • Reduction of disulphide bonds unmasks potent antimicrobial activity of human β-defensin 1.

    abstract::Human epithelia are permanently challenged by bacteria and fungi, including commensal and pathogenic microbiota. In the gut, the fraction of strict anaerobes increases from proximal to distal, reaching 99% of bacterial species in the colon. At colonic mucosa, oxygen partial pressure is below 25% of airborne oxygen con...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature09674

    authors: Schroeder BO,Wu Z,Nuding S,Groscurth S,Marcinowski M,Beisner J,Buchner J,Schaller M,Stange EF,Wehkamp J

    更新日期:2011-01-20 00:00:00

  • Ice loss from the East Antarctic Ice Sheet during late Pleistocene interglacials.

    abstract::Understanding ice sheet behaviour in the geological past is essential for evaluating the role of the cryosphere in the climate system and for projecting rates and magnitudes of sea level rise in future warming scenarios1-4. Although both geological data5-7 and ice sheet models3,8 indicate that marine-based sectors of ...

    journal_title:Nature

    pub_type: 历史文章,杂志文章

    doi:10.1038/s41586-018-0501-8

    authors: Wilson DJ,Bertram RA,Needham EF,van de Flierdt T,Welsh KJ,McKay RM,Mazumder A,Riesselman CR,Jimenez-Espejo FJ,Escutia C

    更新日期:2018-09-01 00:00:00