Abstract:
:The clinical development of an inhibitor of cellular proteasome function suggests that compounds targeting other components of the ubiquitin-proteasome system might prove useful for the treatment of human malignancies. NEDD8-activating enzyme (NAE) is an essential component of the NEDD8 conjugation pathway that controls the activity of the cullin-RING subtype of ubiquitin ligases, thereby regulating the turnover of a subset of proteins upstream of the proteasome. Substrates of cullin-RING ligases have important roles in cellular processes associated with cancer cell growth and survival pathways. Here we describe MLN4924, a potent and selective inhibitor of NAE. MLN4924 disrupts cullin-RING ligase-mediated protein turnover leading to apoptotic death in human tumour cells by a new mechanism of action, the deregulation of S-phase DNA synthesis. MLN4924 suppressed the growth of human tumour xenografts in mice at compound exposures that were well tolerated. Our data suggest that NAE inhibitors may hold promise for the treatment of cancer.
journal_name
Naturejournal_title
Natureauthors
Soucy TA,Smith PG,Milhollen MA,Berger AJ,Gavin JM,Adhikari S,Brownell JE,Burke KE,Cardin DP,Critchley S,Cullis CA,Doucette A,Garnsey JJ,Gaulin JL,Gershman RE,Lublinsky AR,McDonald A,Mizutani H,Narayanan U,Olhava EJdoi
10.1038/nature07884subject
Has Abstractpub_date
2009-04-09 00:00:00pages
732-6issue
7239eissn
0028-0836issn
1476-4687pii
nature07884journal_volume
458pub_type
杂志文章相关文献
NATURE文献大全abstract::The colorectal adenoma-carcinoma sequence has provided a paradigmatic framework for understanding the successive somatic genetic changes and consequent clonal expansions that lead to cancer1. However, our understanding of the earliest phases of colorectal neoplastic changes-which may occur in morphologically normal ti...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/s41586-019-1672-7
更新日期:2019-10-01 00:00:00
abstract::Fusion of myeloma cells and B lymphocytes to form hybridomas which produce monoclonal antibodies has been a major advance, but the poor efficiency and randomness of viral or polyethylene glycol fusion techniques generally gives poor yields of specific, high affinity antibodies. High voltage electrical fields with diel...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/310792a0
更新日期:1984-08-30 00:00:00
abstract::The evolution of self-fertilization in hermaphrodites is opposed by costs that decrease the value of self progeny relative to that of outcross progeny. However, self-fertilization is common in plants; 20% are highly selfing and 33% are intermediate between selfing and outcrossing. Darwin proposed an adaptive benefit o...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature02776
更新日期:2004-08-19 00:00:00
abstract::The guinea-pig (Cavia porcellus), traditionally classified as a New World hystricomorph rodent, often shows anomalous morphological and molecular features in comparison with other eutherian mammals. For example, its insulin differs from that of other mammals in anabolic and growth-promoting activities and in its capab...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/351649a0
更新日期:1991-06-20 00:00:00
abstract::Alzheimer's disease is the world's most common dementing illness. Deposition of amyloid-β peptide drives cerebral neuroinflammation by activating microglia. Indeed, amyloid-β activation of the NLRP3 inflammasome in microglia is fundamental for interleukin-1β maturation and subsequent inflammatory events. However, it r...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature11729
更新日期:2013-01-31 00:00:00
abstract::Butterflies rely extensively on colour vision to adapt to the natural world. Most species express a broad range of colour-sensitive Rhodopsin proteins in three types of ommatidia (unit eyes), which are distributed stochastically across the retina. The retinas of Drosophila melanogaster use just two main types, in whic...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature18616
更新日期:2016-07-14 00:00:00
abstract::Phase and antigenic variation of pilin expression in Neisseria gonorrhoeae result from recombination events in which variant sequences from one of the silent loci (pilS) are transferred to the expression locus (pilE). Such rearrangements were originally thought to be gene conversions, but findings showing that phase v...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/338651a0
更新日期:1989-04-20 00:00:00
abstract::The ability to trap an object-whether a single atom or a macroscopic entity-affects fields as diverse as quantum optics, soft condensed-matter physics, biophysics and clinical medicine. Many sophisticated methodologies have been developed to counter the randomizing effect of Brownian motion in solution, but stable tra...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature09404
更新日期:2010-10-07 00:00:00
abstract::A fascinating question in biology is how molecular changes in developmental pathways lead to macroevolutionary changes in morphology. Mutations in homeotic (Hox) genes have long been suggested as potential causes of morphological evolution, and there is abundant evidence that some changes in Hox expression patterns co...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature716
更新日期:2002-02-21 00:00:00
abstract::The presence of homoeo box sequences in the genomes of vertebrates has suggested that these metazoans possess the equivalent of the homoeotic genes that have a key role in regulating the development of the fruitfly Drosophila melanogaster. We report here that a novel murine homoeo box-containing gene is expressed in e...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/314713a0
更新日期:1985-04-25 00:00:00
abstract::The carotid body type I cell contains amines and has features, both morphological and cytochemical, which indicate that it may also produce a peptide. Many regulatory peptides are now known to be present in both central and peripheral tissues. In the periphery these neuropeptides occur in both classical endocrine (APU...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/284269a0
更新日期:1980-03-20 00:00:00
abstract::Alkaloids, secondary metabolites that contain basic nitrogen atoms, are some of the most well-known biologically active natural products in chemistry and medicine. Although efficient laboratory synthesis of alkaloids would enable the study and optimization of their biological properties, their preparation is often com...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature14902
更新日期:2015-09-24 00:00:00
abstract::The establishment and maintenance of epigenetic gene silencing is fundamental to cell determination and function. The essential epigenetic systems involved in heritable repression of gene activity are the Polycomb group (PcG) proteins and the DNA methylation systems. Here we show that the corresponding silencing pathw...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature04431
更新日期:2006-02-16 00:00:00
abstract::TATA-binding protein (TBP) binds the minor groove of the TATA element with the DNA bent 80 degrees towards the major groove. A constrained minicircle strategy has been used to test the effect of DNA topology on the affinity of TBP for the TATA element. We report here that TBP bound to DNA which was slightly pre-bent t...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/373724a0
更新日期:1995-02-23 00:00:00
abstract::Quantum cryptography exploits the fundamental laws of quantum mechanics to provide a secure way to exchange private information. Such an exchange requires a common random bit sequence, called a key, to be shared secretly between the sender and the receiver. The basic idea behind quantum key distribution (QKD) has wide...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature13303
更新日期:2014-05-22 00:00:00
abstract::Transgenic mice bearing the cellular myc oncogene coupled to the immunoglobulin mu or kappa enhancer frequently develop a fatal lymphoma within a few months of birth. Since the tumours represent represent both immature and mature B lymphocytes, constitutive c-myc expression appears to be highly leukaemogenic at severa...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/318533a0
更新日期:1985-12-12 00:00:00
abstract::Transformation of the well-studied maize transposable elements into other plant species should enable transposon tagging methodology to be used for the isolation of interesting genes in the heterologous host. Here we describe the isolation of a transposon-tagged male sterile mutant in Arabidopsis thaliana using the ma...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/363715a0
更新日期:1993-06-24 00:00:00
abstract::Observations from Earth-orbiting satellites have been a key component in monitoring climate change for the past two decades. This has become possible with the availability of air temperatures from the Microwave Sounding Unit (MSU) since 1979, sea surface temperatures from the Advanced Very High Resolution Radiometer (...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/35000184
更新日期:2000-01-27 00:00:00
abstract::Quantum physics has remarkable distinguishing characteristics. For example, it gives only probabilistic predictions (non-determinism) and does not allow copying of unknown states (no-cloning). Quantum correlations may be stronger than any classical ones, but information cannot be transmitted faster than light (no-sign...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature08400
更新日期:2009-10-22 00:00:00
abstract::Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has infected 78 million individuals and is responsible for over 1.7 million deaths to date. Infection is associated with development of variable levels of antibodies with neutralizing activity that can protect against infection in animal models1,2. Antibody ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/s41586-021-03207-w
更新日期:2021-01-18 00:00:00
abstract::In budding yeast many genes are expressed under cell-cycle control in late G1. These include a large group of DNA synthesis genes, the HO gene involved in mating-type switching, CTS1 (chitinase) and also CLN1 and CLN2 (ref. 4) encoding G1 cyclins. Two factors, encoded by the SWI4 and SWI6 genes, are required for HO (r...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/357505a0
更新日期:1992-06-11 00:00:00
abstract::The current need for novel antibiotics is especially acute for drug-resistant Gram-negative pathogens1,2. These microorganisms have a highly restrictive permeability barrier, which limits the penetration of most compounds3,4. As a result, the last class of antibiotics that acted against Gram-negative bacteria was deve...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/s41586-019-1791-1
更新日期:2019-12-01 00:00:00
abstract::Immunization of male and female animals with extracts of whole sperm cells is known to cause infertility. Also, men and women who spontaneously produce antisperm antibodies are infertile but otherwise healthy. Although the critical sperm antigens are unknown, these observations have led to the proposal that sperm prot...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/335543a0
更新日期:1988-10-06 00:00:00
abstract::The idea that natural selection on genes might be detected using only a single genome has been put forward by Plotkin and colleagues, who present a method that they claim can detect selection without the need for comparative data and which, if correct, would confer greater power of analysis with less information. Here...
journal_title:Nature
pub_type: 评论,杂志文章
doi:10.1038/nature03221
更新日期:2005-01-20 00:00:00
abstract::Presenilin and signal peptide peptidase (SPP) are intramembrane aspartyl proteases that regulate important biological functions in eukaryotes. Mechanistic understanding of presenilin and SPP has been hampered by lack of relevant structural information. Here we report the crystal structure of a presenilin/SPP homologue...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature11801
更新日期:2013-01-03 00:00:00
abstract::The RNA polymerase II large subunit contains an essential carboxy-terminal domain (CTD) believed to be involved in the response to regulators during transcription initiation. The CTD is phosphorylated on a portion of RNA polymerase II molecules in vivo and it can be phosphorylated by the general transcription factor T...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/374280a0
更新日期:1995-03-16 00:00:00
abstract::Activation of RIPK1 controls TNF-mediated apoptosis, necroptosis and inflammatory pathways1. Cleavage of human and mouse RIPK1 after residues D324 and D325, respectively, by caspase-8 separates the RIPK1 kinase domain from the intermediate and death domains. The D325A mutation in mouse RIPK1 leads to embryonic lethali...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/s41586-019-1830-y
更新日期:2020-01-01 00:00:00
abstract::The biosynthesis of several protein cofactors is subject to feedback regulation by riboswitches. Flavin mononucleotide (FMN)-specific riboswitches, also known as RFN elements, direct expression of bacterial genes involved in the biosynthesis and transport of riboflavin (vitamin B(2)) and related compounds. Here we pre...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature07642
更新日期:2009-03-12 00:00:00
abstract::A 12 amino-acid synthetic peptide (NANP)3 comprising the immunodominant epitope of Plasmodium falciparum circumsporozoite protein was conjugated to tetanus toxoid (TT), adjuvanted with aluminium hydroxide, and administered intramuscularly in three doses at monthly intervals to 35 healthy males as a malaria vaccine. No...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/328257a0
更新日期:1987-07-16 00:00:00
abstract::Non-small-cell lung cancer is the leading cause of cancer-related death worldwide. Chemotherapies such as the topoisomerase II (TopoII) inhibitor etoposide effectively reduce disease in a minority of patients with this cancer; therefore, alternative drug targets, including epigenetic enzymes, are under consideration f...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature14122
更新日期:2015-04-09 00:00:00