Abstract:
:Activating mutations in BRAF are found in 50% of melanomas and although treatment with BRAF inhibitors (BRAFi) is effective, resistance often develops. We now show that recently discovered NRAS isoform 2 is up-regulated in the setting of BRAF inhibitor resistance in melanoma, in both cell lines and patient tumor tissues. When isoform 2 was overexpressed in BRAF mutant melanoma cell lines, melanoma cell proliferation and in vivo tumor growth were significantly increased in the presence of BRAFi treatment. shRNA-mediated knockdown of isoform 2 in BRAFi resistant cells restored sensitivity to BRAFi compared with controls. Signaling analysis indicated decreased mitogen-activated protein kinase (MAPK) pathway signaling and increased phosphoinositol-3-kinase (PI3K) pathway signaling in isoform 2 overexpressing cells compared with isoform 1 overexpressing cells. Immunoprecipitation of isoform 2 validated a binding affinity of this isoform to both PI3K and BRAF/RAF1. The addition of an AKT inhibitor to BRAFi treatment resulted in a partial restoration of BRAFi sensitivity in cells expressing high levels of isoform 2. NRAS isoform 2 may contribute to resistance to BRAFi by facilitating PI3K pathway activation.
journal_name
Proc Natl Acad Sci U S Aauthors
Duggan MC,Stiff AR,Bainazar M,Regan K,Olaverria Salavaggione GN,Maharry S,Blachly JS,Krischak M,Walker CJ,Latchana N,Tridandapani S,de la Chapelle A,Eisfeld AK,Carson WE 3rddoi
10.1073/pnas.1704371114subject
Has Abstractpub_date
2017-09-05 00:00:00pages
9629-9634issue
36eissn
0027-8424issn
1091-6490pii
1704371114journal_volume
114pub_type
杂志文章abstract::The antitumor drug Taxol stabilizes microtubules and reduces their dynamicity, promoting mitotic arrest and cell death. Upon assembly of the alpha/beta-tubulin heterodimer, GTP bound to beta-tubulin is hydrolyzed to GDP reaching a steady-state equilibrium between free tubulin dimers and microtubules. The binding of Ta...
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.0603704103
更新日期:2006-07-05 00:00:00
abstract::Molecular beacons are DNA probes that form a stem-and-loop structure and possess an internally quenched fluorophore. When they bind to complementary nucleic acids, they undergo a conformational transition that switches on their fluorescence. These probes recognize their targets with higher specificity than probes 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.96.11.6171
更新日期:1999-05-25 00:00:00
abstract::Plants frequently respond to herbivorous insect attack by synthesizing defense proteins that deter insect feeding and prevent additional herbivory. Maize (Zea mays L.) lines, resistant to feeding by a number of lepidopteran species, rapidly mobilize a unique 33-kDa cysteine protease in response to caterpillar feeding....
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.202224899
更新日期:2002-10-01 00:00:00
abstract::Recently the definition of the metazoan RNA polymerase II and archaeal core promoters has been expanded to include a region immediately upstream of the TATA box called the B recognition element (BRE), so named because eukaryal transcription factor TFIIB and its archaeal orthologue TFB interact with the element in a se...
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.96.24.13668
更新日期:1999-11-23 00:00:00
abstract::The unicellular green alga Chlamydomonas swims with two flagella that can synchronize their beat. Synchronized beating is required to swim both fast and straight. A long-standing hypothesis proposes that synchronization of flagella results from hydrodynamic coupling, but the details are not understood. Here, we presen...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
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更新日期:2013-11-05 00:00:00
abstract::Beckwith-Wiedemann syndrome (BWS) involves fetal overgrowth and predisposition to a wide variety of embryonal tumors of childhood. We have previously found that BWS is genetically linked to 11p15 and that this same band shows loss of heterozygosity in the types of tumors to which children with BWS are susceptible. How...
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.92.26.12456
更新日期:1995-12-19 00:00:00
abstract::Charge transport (CT) through the DNA base pairs provides a means to promote redox reactions at a remote site and potentially to effect signaling between molecules bound to DNA. Here we describe the oxidation of a cell-cycle regulatory protein, p53, from a distance through DNA-mediated CT. A consensus p53 binding site...
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.0709326104
更新日期:2007-11-27 00:00:00
abstract::Transgenic overexpression of Cu(+2)/Zn(+2) superoxide dismutase 1 (SOD1) harboring an amyotrophic lateral sclerosis (ALS)-linked familial genetic mutation (SOD1(G93A)) in a Sprague-Dawley rat results in ALS-like motor neuron disease. Motor neuron disease in these rats depended on high levels of mutant SOD1 expression,...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
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更新日期:2002-02-05 00:00:00
abstract::Tubular membrane structures are widespread in eukaryotic cells, but the mechanisms underlying their formation and stability are not well understood. Previous work has focused on tube extrusion from cells and model membranes under the application of external forces. Here, we present novel membrane/polymer systems, wher...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
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更新日期:2011-03-22 00:00:00
abstract::More than two decades ago, the activation mechanism for the membrane-bound photoreceptor and prototypical G protein-coupled receptor (GPCR) rhodopsin was uncovered. Upon light-induced changes in ligand-receptor interaction, movement of specific transmembrane helices within the receptor opens a crevice at the cytoplasm...
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.1721896115
更新日期:2018-03-06 00:00:00
abstract::B-cell translocation gene 3 (BTG3) is a member of the antiproliferative BTG/ Transducer of ErbB2 gene family and is induced by genotoxic stress in a p53- and Checkpoint kinase 1 (CHK1)-dependent manner. Down-regulation of BTG3 has been observed in human cancers, suggesting that it plays an important role in tumor supp...
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.1220635110
更新日期:2013-04-09 00:00:00
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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.190066697
更新日期:2000-09-26 00:00:00
abstract::Phosphocholine (PC) is an abundant primary form of organic phosphate that is transported in plant xylem sap. Addition of PC to the perfusate of compressed Pi-starved sycamore cells monitored by 31P NMR spectroscopy resulted in an accumulation of PC and all the other phosphate esters in the cytoplasmic compartment. Add...
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.87.11.4280
更新日期:1990-06-01 00:00:00
abstract::Single molecule atomic force microscopy was used to characterize structure, binding strength (unbinding force), and binding kinetics of a classical cadherin, vascular endothelial (VE)-cadherin, secreted by transfected Chinese hamster ovary cells as cis-dimerized full-length external domain fused to Fc-portion of human...
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.070052697
更新日期:2000-04-11 00:00:00
abstract::Spermatogonia are the male germ stem cells that continuously produce sperm for the next generation. Spermatogenesis is a complicated process that proceeds through mitotic phase of stem cell renewal and differentiation, meiotic phase, and postmeiotic phase of spermiogenesis. Full recapitulation of spermatogenesis in vi...
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.0308668101
更新日期:2004-05-25 00:00:00
abstract::The lateral neural plate border (NPB), the neural part of the vertebrate neural border, is composed of central nervous system (CNS) progenitors and peripheral nervous system (PNS) progenitors. In invertebrates, PNS progenitors are also juxtaposed to the lateral boundary of the CNS. Whether there are conserved molecula...
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.1704194114
更新日期:2017-08-01 00:00:00
abstract::Differential scanning microcalorimetry provides a noninvasive method for studying heat evolution in living cells. We used this technique to measure the heat evolved by thioglycollate broth-elicited mouse macrophages, and the effects of NaF, KCN, cycloheximide, and cytochalasins B and D on this parameter. The total hea...
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.78.10.5958
更新日期:1981-10-01 00:00:00
abstract::Here, we report the isolation and characterization of an endogenous peptide ligand of GPR103 from rat brains. The purified peptide was found to be the 43-residue RF-amide peptide QRFP. We also describe two mouse homologues of human GPR103, termed mouse GPR103A and GPR103B. QRFP binds and activates the human GPR103, as...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
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更新日期:2006-05-09 00:00:00
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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doi:10.1073/pnas.1607570113
更新日期:2016-10-25 00:00:00
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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.95.16.9274
更新日期:1998-08-04 00:00:00
abstract::The phosphorylation of H2Ax on its S139 site, γH2Ax, is important during DNA double-strand repair and is considered necessary for assembly of repair complexes, but its functional role after other kinds of DNA damage is less clear. We have measured the survival of isogenic mouse cell lines with the H2Ax gene knocked ou...
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.1105866108
更新日期:2011-05-24 00:00:00
abstract::Genomic analyses of patients with congenital heart disease (CHD) have identified significant contribution from mutations affecting cilia genes and chromatin remodeling genes; however, the mechanism(s) connecting chromatin remodeling to CHD is unknown. Histone H2B monoubiquitination (H2Bub1) is catalyzed by the RNF20 c...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
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更新日期:2019-07-09 00:00:00
abstract::We report the discovery in Lake Cuitzeo in central Mexico of a black, carbon-rich, lacustrine layer, containing nanodiamonds, microspherules, and other unusual materials that date to the early Younger Dryas and are interpreted to result from an extraterrestrial impact. These proxies were found in a 27-m-long core as p...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 历史文章,杂志文章
doi:10.1073/pnas.1110614109
更新日期:2012-03-27 00:00:00
abstract::Cancer immunotherapy has emerged as a promising therapeutic intervention. However, complete and durable responses are only seen in a fraction of patients who have cancer. A key factor that limits therapeutic success is the infiltration of tumors by cells of the myeloid lineage. The inhibitory receptor signal regulator...
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.1710877114
更新日期:2017-12-05 00:00:00
abstract::The importance of dystrophin and its associated proteins in normal muscle function is now well established. Many of these proteins are expressed in nonmuscle tissues, particularly the brain. Here we describe the characterization of beta-dystrobrevin, a dystrophin-related protein that is abundantly expressed in brain a...
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.95.1.241
更新日期:1998-01-06 00:00:00
abstract::Recent evidence suggests that the Myc and Mad1 proteins are implicated in the regulation of the gene encoding the human telomerase reverse transcriptase (hTERT), the catalytic subunit of telomerase. We have analyzed the in vivo interaction between endogenous c-Myc and Mad1 proteins and the hTERT promoter in HL60 cells...
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.071043198
更新日期:2001-03-27 00:00:00
abstract::The symbiotic bacterium Wolbachia pipientis has been considered unique in its ability to cause multiple reproductive anomalies in its arthropod hosts. Here we report that an undescribed bacterium is vertically transmitted and associated with thelytokous parthenogenetic reproduction in Encarsia, a genus of parasitoid 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.221467498
更新日期:2001-10-23 00:00:00
abstract::A general and efficient method has been developed to generate large numbers of single-base substitution mutations simply and rapidly. A unique f1 phage recombinant DNA cloning vector is described, which contains the phi X174 origin of viral strand DNA synthesis and allows one to direct mutagenesis to any specific segm...
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.81.7.2030
更新日期:1984-04-01 00:00:00
abstract::Phosphorylation plays a critical role in controlling the function of cytoskeletal assemblies but no direct method yet exists to measure the phosphorylation state of proteins at the level of individual molecules and assemblies. Herein, we apply scanning transmission electron microscopy in combination with electron ener...
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.94.15.7820
更新日期:1997-07-22 00:00:00
abstract::E2F is a cellular transcription factor that binds to two sites in the adenovirus E2 promoter. Previous experiments have implicated E2F in the E1A-dependent transactivation of the E2 gene since levels of active E2F increase markedly during adenovirus infection in parallel with the increase in E2 transcription, and an E...
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.86.10.3594
更新日期:1989-05-01 00:00:00