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
Naturejournal_title
Natureauthors
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 LIdoi
10.1038/nature09882subject
Has Abstractpub_date
2011-03-24 00:00:00pages
518-22issue
7339eissn
0028-0836issn
1476-4687pii
nature09882journal_volume
471pub_type
杂志文章相关文献
NATURE文献大全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
更新日期:2005-08-18 00:00:00
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
更新日期:2006-10-05 00:00:00
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
更新日期:2018-10-01 00:00:00
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
更新日期:2004-05-06 00:00:00
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
更新日期:2015-01-15 00:00:00
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
更新日期:1990-11-01 00:00:00
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
更新日期:1999-07-22 00:00:00
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
更新日期:2002-03-21 00:00:00
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
更新日期:2002-09-19 00:00:00
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
更新日期:1983-11-10 00:00:00
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
更新日期:2016-02-18 00:00:00
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
更新日期:2001-02-15 00:00:00
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
更新日期:2002-01-31 00:00:00
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
更新日期:2016-08-11 00:00:00
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
更新日期:2011-05-19 00:00:00
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
更新日期:2000-09-14 00:00:00
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
更新日期:1983-02-10 00:00:00
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
更新日期:2016-11-10 00:00:00
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
更新日期:2002-11-07 00:00:00
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
更新日期:1982-07-01 00:00:00
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
更新日期:2002-01-24 00:00:00
abstract:: ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/d41586-018-07511-w
更新日期:2018-11-01 00:00:00
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
更新日期:1985-05-30 00:00:00
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
更新日期:1988-11-24 00:00:00
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
更新日期:1991-03-07 00:00:00
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
更新日期:2005-03-24 00:00:00
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
更新日期:1980-05-15 00:00:00
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
更新日期:1975-12-25 00:00:00
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
更新日期:2011-01-20 00:00:00
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
更新日期:2018-09-01 00:00:00