Abstract:
:Activation of oncogenes by mechanisms other than genetic aberrations such as mutations, translocations, or amplifications is largely undefined. Here we report a novel isoform of the anaplastic lymphoma kinase (ALK) that is expressed in ∼11% of melanomas and sporadically in other human cancer types, but not in normal tissues. The novel ALK transcript initiates from a de novo alternative transcription initiation (ATI) site in ALK intron 19, and was termed ALK(ATI). In ALK(ATI)-expressing tumours, the ATI site is enriched for H3K4me3 and RNA polymerase II, chromatin marks characteristic of active transcription initiation sites. ALK(ATI) is expressed from both ALK alleles, and no recurrent genetic aberrations are found at the ALK locus, indicating that the transcriptional activation is independent of genetic aberrations at the ALK locus. The ALK(ATI) transcript encodes three proteins with molecular weights of 61.1, 60.8 and 58.7 kilodaltons, consisting primarily of the intracellular tyrosine kinase domain. ALK(ATI) stimulates multiple oncogenic signalling pathways, drives growth-factor-independent cell proliferation in vitro, and promotes tumorigenesis in vivo in mouse models. ALK inhibitors can suppress the kinase activity of ALK(ATI), suggesting that patients with ALK(ATI)-expressing tumours may benefit from ALK inhibitors. Our findings suggest a novel mechanism of oncogene activation in cancer through de novo alternative transcription initiation.
journal_name
Naturejournal_title
Natureauthors
Wiesner T,Lee W,Obenauf AC,Ran L,Murali R,Zhang QF,Wong EW,Hu W,Scott SN,Shah RH,Landa I,Button J,Lailler N,Sboner A,Gao D,Murphy DA,Cao Z,Shukla S,Hollmann TJ,Wang L,Borsu L,Merghoub T,Schwartz GK,Postow MAdoi
10.1038/nature15258subject
Has Abstractpub_date
2015-10-15 00:00:00pages
453-7issue
7573eissn
0028-0836issn
1476-4687pii
nature15258journal_volume
526pub_type
杂志文章相关文献
NATURE文献大全abstract::In Dictyostelium discoideum, carbohydrate binding proteins (CBPs) or lectins have been implicated in the molecular basis of cellular cohesion. To determine the role of these CBPs, we have attempted to isolate structural gene mutants in which the CBPs have a defective affinity for carbohydrate ligands. We now report th...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/279215a0
更新日期:1979-05-17 00:00:00
abstract::Although there are substantial differences between the magnetospheres of Jupiter and Saturn, it has been suggested that cryovolcanic activity at Enceladus could lead to electrodynamic coupling between Enceladus and Saturn like that which links Jupiter with Io, Europa and Ganymede. Powerful field-aligned electron beams...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature09928
更新日期:2011-04-21 00:00:00
abstract::Most Oryza sativa cultivars die within a week of complete submergence--a major constraint to rice production in south and southeast Asia that causes annual losses of over US 1 billion dollars and affects disproportionately the poorest farmers in the world. A few cultivars, such as the O. sativa ssp. indica cultivar FR...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature04920
更新日期:2006-08-10 00:00:00
abstract::Cutaneous malignant melanoma is a highly aggressive and frequently chemoresistant cancer, the incidence of which continues to rise. Epidemiological studies show that the major aetiological melanoma risk factor is ultraviolet (UV) solar radiation, with the highest risk associated with intermittent burning doses, especi...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature09666
更新日期:2011-01-27 00:00:00
abstract::Solitons-solitary waves that maintain their shape as they propagate-occur as water waves in narrow canals, as light pulses in optical fibres and as quantum mechanical matter waves in superfluids and superconductors. Their highly nonlinear and localized nature makes them very sensitive probes of the medium in which the...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature12338
更新日期:2013-07-25 00:00:00
abstract::Transmembrane sodium-ion gradients provide energy that can be harnessed by 'secondary transporters' to drive the translocation of solute molecules into a cell. Decades of study have shown that such sodium-coupled transporters are involved in many physiological processes, making them targets for the treatment of numero...
journal_title:Nature
pub_type: 杂志文章,评审
doi:10.1038/nature08143
更新日期:2009-05-21 00:00:00
abstract::Ribosome-driven protein biosynthesis is comprised of four phases: initiation, elongation, termination and recycling. In bacteria, ribosome recycling requires ribosome recycling factor and elongation factor G, and several structures of bacterial recycling complexes have been determined. In the eukaryotic and archaeal k...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature10829
更新日期:2012-02-22 00:00:00
abstract::A hemispheric dichotomy on Mars is marked by the sharp contrast between the sparsely cratered northern lowland plains and the heavily cratered southern highlands. Mechanisms proposed to remove ancient crust or form younger lowland crust include one or more giant impacts, subcrustal transport by mantle convection, the ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature05356
更新日期:2006-12-14 00:00:00
abstract::The ability of collapsing (cavitating) bubbles to focus and concentrate energy, forces and stresses is at the root of phenomena such as cavitation damage, sonochemistry or sonoluminescence. In a biomedical context, ultrasound-driven microbubbles have been used to enhance contrast in ultrasonic images. The observation ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature01613
更新日期:2003-05-08 00:00:00
abstract::Outbreaks of haemorrhagic fever caused by the Ebola virus are associated with high mortality rates that are a distinguishing feature of this human pathogen. The highest lethality is associated with the Zaire subtype, one of four strains identified to date. Its rapid progression allows little opportunity to develop nat...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/35046108
更新日期:2000-11-30 00:00:00
abstract::Long-term synaptic potentiation (LTP) is thought to be a key process in cortical synaptic network plasticity and memory formation. Hebbian forms of LTP depend on strong postsynaptic depolarization, which in many models is generated by action potentials that propagate back from the soma into dendrites. However, local d...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature13664
更新日期:2014-11-06 00:00:00
abstract::In photoreceptors, a latency of many milliseconds elapses between the absorption of a light quantum and the occurrence of the late receptor potential, even for strong light stimuli. Surprisingly, this is much longer than the time necessary for conductance changes such as occur in membranes of neurones or muscles, medi...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/283859a0
更新日期:1980-02-28 00:00:00
abstract::Retinoid X receptor (RXR) plays a central role in the regulation of many intracellular receptor signalling pathways and can mediate ligand-dependent transcription, acting as a homodimer or as a heterodimer. Here we identify an antagonist towards RXR homodimers which also functions as an agonist when RXR is paired as a...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/383450a0
更新日期:1996-10-03 00:00:00
abstract::Certain mast cell products, including the tetrapeptides Ala-Gly-Ser-Glu (Ala4) and Val-Gly-Ser-Glu (Val4) of the eosinophil chemotactic factor of anaphylaxis (ECF-A) and histamine, are preferentially chemotactic for eosinophils in vitro. Amino acid substitutions or modifications of the ECF-A tetrapeptides may substant...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/289071a0
更新日期:1981-01-01 00:00:00
abstract::X-linked spinal and bulbar muscular atrophy (Kennedy's disease) is an adult-onset form of motorneuron disease which may be associated with signs of androgen insensitivity. We have now investigated whether the androgen receptor gene on the proximal long arm of the X chromosome is a candidate gene for this disease. In p...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/352077a0
更新日期:1991-07-04 00:00:00
abstract::Spontaneous mutations are the source of genetic variation required for evolutionary change, and are therefore important for many aspects of evolutionary biology. For example, the divergence between taxa at neutrally evolving sites in the genome is proportional to the per nucleotide mutation rate, u (ref. 1), and this ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature05388
更新日期:2007-01-04 00:00:00
abstract::The debate over human origins has focused on two competing theories. The single African origin model holds that anatomically modern Homo sapiens evolved in Africa 100,000-200,000 years ago. Members of this population migrated out of Africa, replacing archaic human groups through Asia and Europe, with racial differenti...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/368452a0
更新日期:1994-03-31 00:00:00
abstract::Neurotransmitter release is initiated by influx of Ca2+ through voltage-gated Ca2+ channels, within 200 microseconds of the action potential arriving at the synaptic terminal, as the Ca2+ concentration increases from 100 nM to > 200 microM. Exocytosis requires high Ca2+ concentration, with a threshold of 20-50 microM ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/379451a0
更新日期:1996-02-01 00:00:00
abstract::RNase P is the only endonuclease responsible for processing the 5' end of transfer RNA by cleaving a precursor and leading to tRNA maturation. It contains an RNA component and a protein component and has been identified in all organisms. It was one of the first catalytic RNAs identified and the first that acts as a mu...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature01386
更新日期:2003-02-13 00:00:00
abstract::It has been established that many eukaryotic mRNAs contain poly(adenylic acid) tracts at their 3'-termini. The polyadenylation of mRNA occurs post-transcriptionally in the nucleus as a rapid, initial addition of 100-200 adenylate residues to the pre-mRNA (ref. 1). Subsequently, a slower chain extension (6-8 bases) of ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/267178a0
更新日期:1977-05-12 00:00:00
abstract::In magnetic memory devices, logical bits are recorded by selectively setting the magnetization vector of individual magnetic domains either 'up' or 'down'. In such devices, the fastest and most efficient recording method involves precessional switching: when a magnetic field B(p) is applied as a write pulse over a per...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature02438
更新日期:2004-04-22 00:00:00
abstract::Observations show that the seismic normal modes of the Earth at frequencies near 10 mHz are excited at a nearly constant level in the absence of large earthquakes. This background level of excitation has been called the 'hum' of the Earth, and is equivalent to the maximum excitation from a magnitude 5.75 earthquake. I...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature05536
更新日期:2007-02-15 00:00:00
abstract::One of the most debated questions in evolutionary biology is whether female choice of males with exaggerated sexual displays can evolve as a correlated response to selection acting on genes coding for male attractiveness or high overall viability. To date, empirical studies have provided support for parts of this scen...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature04564
更新日期:2006-05-04 00:00:00
abstract::Concentrating urine is mandatory for most mammals to prevent water loss from the body. Concentrated urine is produced in response to vasopressin by the transepithelial recovery of water from the lumen of the kidney collecting tubule through highly water-permeable membranes. In this nephron segment, vasopressin regulat...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/361549a0
更新日期:1993-02-11 00:00:00
abstract::Volatile anaesthetics have historically been considered to act in a nonspecific manner on the central nervous system. More recent studies, however, have revealed that the receptors for inhibitory neurotransmitters such as gamma-aminobutyric acid (GABA) and glycine are sensitive to clinically relevant concentrations of...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/38738
更新日期:1997-09-25 00:00:00
abstract::Climate models with increased levels of carbon dioxide predict that global warming causes heating in the tropics, but investigations of ancient climates based on palaeodata have generally indicated cool tropical temperatures during supposed greenhouse episodes. For example, in the Late Cretaceous and Eocene epochs the...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/35097000
更新日期:2001-10-04 00:00:00
abstract::Cryo-electron microscopy (cryo-EM) has the capacity to capture molecular machines in action1-3. ATP-binding cassette (ABC) exporters are highly dynamic membrane proteins that extrude a wide range of substances from the cytosol4-6 and thereby contribute to essential cellular processes, adaptive immunity and multidrug r...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/s41586-019-1391-0
更新日期:2019-07-01 00:00:00
abstract::Peroxisomes are among the intracellular organelles of eukaryotic cells that contain specialized sets of enzymes with specific functions. Little is known of membranous components involved in assembly of the intracellular compartments. We isolated two peroxisome-deficient and mutually complementary, Chinese hamster ovar...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/350077a0
更新日期:1991-03-07 00:00:00
abstract::Oxygen isotope analyses of Spondylus shells from neolithic sites suggest that the source for the shells used as ornaments in the Balkans and central Europe during the fourth millennium BC was the Aegean and not the Black Sea. The trade in Spondylus may have taken the form of an exchange of gifts. ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/2281062a0
更新日期:1970-12-12 00:00:00
abstract::It has been shown that Neanderthals contributed genetically to modern humans outside Africa 47,000-65,000 years ago. Here we analyse the genomes of a Neanderthal and a Denisovan from the Altai Mountains in Siberia together with the sequences of chromosome 21 of two Neanderthals from Spain and Croatia. We find that a p...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature16544
更新日期:2016-02-25 00:00:00