Abstract:
:The binding of small molecules to distinctive three-dimensional structures in mRNA provides a new dimension in RNA control, previously limited to the targeting of secondary structures with antisense and RNA interference; such targeting can modulate mRNA function and rates of protein biosynthesis. Small molecules that selectively bind the iron-responsive element (IRE), a specific three-dimensional structure in the noncoding region of the ferritin mRNA model that is recognized by the iron-regulatory protein repressor, were identified by using chemical footprinting. The assay used involved an oxoruthenium(IV) complex that oxidizes guanine bases in RNA sequences. Small molecules that blocked oxidation of guanines in the internal loop region were expected to selectively increase the rate of ferritin synthesis, because the internal loop region of the ferritin IRE is distinctive from those of other IREs. The natural product yohimbine was found (based on gel mobility shifts) to block cleavage of the internal loop RNA site by >50% and seemed to inhibit protein binding. In the presence of yohimbine, the rate of biosynthesis of ferritin in a cell-free expression system (rabbit reticulocyte lysate) increased by 40%. Assignment of the IRE-yohimbine interaction as the origin of this effect was supported by a similar increase in synthesis of luciferase protein in a chimera of the IRE and luciferase gene. The identification of a small, drug-like molecule that recognizes a naturally occurring three-dimensional mRNA structure and regulates protein biosynthesis rates raises the possibility that small molecules can regulate protein biosynthesis by selectively binding to mRNA.
journal_name
Proc Natl Acad Sci U S Aauthors
Tibodeau JD,Fox PM,Ropp PA,Theil EC,Thorp HHdoi
10.1073/pnas.0509744102keywords:
subject
Has Abstractpub_date
2006-01-10 00:00:00pages
253-7issue
2eissn
0027-8424issn
1091-6490pii
0509744102journal_volume
103pub_type
杂志文章abstract::Prokaryotic genomes are substantially diverse, even when from closely related species, with the resulting phenotypic diversity representing a repertoire of adaptations to specific constraints. Within the microbial population, genome content may not be fixed, as changing selective forces favor particular phenotypes; ho...
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.1735481100
更新日期:2003-11-11 00:00:00
abstract::Fish stocks experiencing high fishing mortality show a tendency to mature earlier and at a smaller size, which may have a genetic component and therefore long-lasting economic and biological effects. To date, the economic effects of such ecoevolutionary dynamics have not been empirically investigated. Using 70 y of da...
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.1212593110
更新日期:2013-07-23 00:00:00
abstract::The c-fos protooncogene is transcriptionally activated by a wide variety of agents including serum, growth factors, and phorbol esters. This induction is rapid and transient and is mediated through a number of identified promoter elements. Growth hormone (GH) is also known to induce transcription of c-fos in a variety...
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.90.14.6721
更新日期:1993-07-15 00:00:00
abstract::A stable complex between pentaammineruthenium(III) and histidine-33 in horse heart ferricytochrome c is formed in the reaction between aquopentaammineruthenium(II) and the protein at pH 7. HPLC of the tryptic hydrolysate of the modified protein was employed to identify the pentaammineruthenium binding site. Spectrosco...
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.79.22.7052
更新日期:1982-11-01 00:00:00
abstract::Recent studies of human disease and transgenic animal experiments have clearly demonstrated the importance of desmosomes in normal tissue architecture. Furthermore, desmosomal components are down-regulated in certain types of carcinomas, suggesting a possible role for desmosomes in suppression of invasion and metastas...
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.95.14.8064
更新日期:1998-07-07 00:00:00
abstract::Aqueous gel sieving chromatography on Sephadex G-10 of the Group IA cations (Li+, Na+, K+, Rb+, Cs+) plus NH4+ as the Cl- salts, in combination with previous results for the halide anions (F-, Cl-, Br-, I-) as the Na+ salts [Washabaugh, M.W. & Collins, K.D. (1986) J. Biol. Chem. 261, 12477-12485], leads to the followi...
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.92.12.5553
更新日期:1995-06-06 00:00:00
abstract::Engagement of the T cell antigen receptor (TCR) leads to rapid activation of protein tyrosine kinases, which in turn phosphorylate downstream enzymes and adapter proteins. Some adapter proteins, such as SLP-76, Vav, and LAT, positively regulate TCR-mediated signal transduction, whereas others, such as Cbl, play an inh...
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.96.17.9775
更新日期:1999-08-17 00:00:00
abstract::We have measured the fidelity of bidirectional, semiconservative DNA synthesis by a human DNA replication complex in vitro. Replication was performed by extracts of HeLa cells in the presence of simian virus 40 (SV40) large tumor antigen by using a double-stranded phage M13mp2 DNA template containing the SV40 origin o...
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.85.19.7064
更新日期:1988-10-01 00:00:00
abstract::The elevation of Ca2+ levels in the cytoplasm inactivates inward-rectifying K+ channels that play a central role in regulating the apertures of stomatal pores in higher plants. However, the mechanism for the Ca(2+)-mediated inhibition of K(+)-channel function is unknown. Using patch-clamp techniques, we show that cycl...
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.90.6.2202
更新日期:1993-03-15 00:00:00
abstract::Trial electron density functions have some conceptual and computational advantages over wave functions. The properties of some simple density functions for H(+) (2) and H(2) are examined. It appears that for a diatomic molecule a good density function would be given by rho = N(A(2) + B(2)), in which A and B are short ...
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.77.4.1725
更新日期:1980-04-01 00:00:00
abstract::Although the first observations of the inhibitory effect of methylation on gene activity were made almost a decade ago, the mechanism by which methyl groups affect transcription is still obscure. Here we use engineered promoters methylated in vitro in transient transfections to study the mechanism by which methylation...
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.89.21.10119
更新日期:1992-11-01 00:00:00
abstract::Monoclonal antibodies can block cellular interactions that negatively regulate T-cell immune responses, such as CD80/CTLA-4 and PD-1/PD1-L, amplifying preexisting immunity and thereby evoking antitumor immune responses. Ibrutinib, an approved therapy for B-cell malignancies, is a covalent inhibitor of BTK, a member of...
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.1500712112
更新日期:2015-03-03 00:00:00
abstract::Understanding the factors that shape macroevolutionary patterns in functional traits is a central goal of evolutionary biology. Alternative strategies of sexual reproduction (inbreeding vs. outcrossing) have divergent effects on population genetic structure and could thereby broadly influence trait evolution. However,...
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.1213867110
更新日期:2013-03-05 00:00:00
abstract::The sea anemone, Nematostella vectensis, has become an attractive new model organism for comparative genomics and evolutionary developmental biology. Over the last few years, many genes have been isolated and their expression patterns studied to gain insight into their function. More recently, functional tools have be...
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.0909148107
更新日期:2010-01-05 00:00:00
abstract::Breakage-fusion-bridge (BFB) is a mechanism of genomic instability characterized by the joining and subsequent tearing apart of sister chromatids. When this process is repeated during multiple rounds of cell division, it leads to patterns of copy number increases of chromosomal segments as well as fold-back inversions...
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.1220977110
更新日期:2013-04-02 00:00:00
abstract::The 158,000 Mr protein, previously designated C5c, present in fully assembled complement (C) membrane attack complexes (MC5b-9) has been identified as a disulfide-bonded dimer of C9. This conclusion was based on the observations that: (i) a portion of the 125I-radiolabeled precursor C9 incorporated into MC5b-9 complex...
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.78.10.6426
更新日期:1981-10-01 00:00:00
abstract::We have examined the role of cyclooxygenase 2 (COX-2) in a model of inflammation in vivo. Carrageenan administration to the subcutaneous rat air pouch induces a rapid inflammatory response characterized by high levels of prostaglandins (PGs) and leukotrienes in the fluid exudate. The time course of the induction of CO...
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.91.8.3228
更新日期:1994-04-12 00:00:00
abstract::We identify a gene, organ boundary1 (OBO1), by its unique pattern of enhancer- driven GFP expression at the boundaries between the apical meristems and lateral organs in Arabidopsis embryos, seedlings, and mature plants. OBO1 also is expressed at the root apical meristem and in distinct cell files surrounding this are...
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.1018542108
更新日期:2011-02-01 00:00:00
abstract::p21Sdi1 (also known as Cip1 and Waf1), an inhibitor of DNA synthesis cloned from senescent human fibroblasts, is an inhibitor of G1 cyclin-dependent kinases (Cdks) in vitro and is transcriptionally regulated by wild-type p53. In addition, p21Sdi1 has been found to inhibit DNA replication by direct interaction with pro...
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.92.10.4352
更新日期:1995-05-09 00:00:00
abstract::Targeted disruption of the pp60(src) (Src) gene has implicated this tyrosine kinase in osteoclast-mediated bone resorption and as a therapeutic target for the treatment of osteoporosis and other bone-related diseases. Herein we describe the discovery of a nonpeptide inhibitor (AP22408) of Src that demonstrates in vivo...
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.97.17.9373
更新日期:2000-08-15 00:00:00
abstract::In the United States, the iconic groundfish fishery for Gulf of Maine cod has endured several dramatic reductions in annual catch limits and been federally declared an economic disaster. Using a repeated cross-sectional survey of fishing captains to assess potential social impacts of the fishery failure, we found 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.1913914116
更新日期:2019-11-12 00:00:00
abstract::The potential benefits of autonomous systems are obvious. However, there are still major issues to be dealt with before developing such systems becomes a commonplace engineering practice, with accepted and trustworthy deliverables. We argue that a solid, evolving, publicly available, community-controlled foundation fo...
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.2003162117
更新日期:2020-07-28 00:00:00
abstract::A dinuclear nickel complex with methyl and thiolate ligands, Ni(dadt(Et))Ni(Me)(SDmp) (2), has been synthesized as a dinuclear Ni(d)-Ni(p)-site model of acetyl-CoA synthase (ACS) (dadt(Et) is N,N'-diethyl-3,7-diazanonane-1,9-dithiolate; Dmp is 2,6-dimesitylphenyl). Complex 2 was prepared via 2 methods: (i) ligand subs...
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.0900433106
更新日期:2009-07-21 00:00:00
abstract::We show that the stimulation of human immunodeficiency virus (HIV) brought about by tumor necrosis factor alpha and phorbol 12-myristate 13-acetate can be inhibited by adding N-acetyl-L-cysteine (NAC). NAC, which replenishes intracellular glutathione, effectively inhibits the tumor necrosis factor alpha- or phorbol es...
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.87.12.4884
更新日期:1990-06-01 00:00:00
abstract::Seven morphologically nontransformed (flat) revertants with reduced tumorigenicity in vivo have been isolated from populations of Kirsten sarcoma virus-transformed NIH 3T3 cells transfected with a cDNA expression library of normal human fibroblasts. Each revertant harbors 1-10 recombinant plasmids per cell and retains...
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.86.1.162
更新日期:1989-01-01 00:00:00
abstract::It was previously shown that coexpression of the lactose permease of Escherichia coli in two contiguous fragments leads to functional complementation. We demonstrate here that site-directed thiol crosslinking of coexpressed permease fragments can be used to determine helix proximity in situ without the necessity of pu...
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.93.25.14498
更新日期:1996-12-10 00:00:00
abstract::The molecular size and stability of the nerve growth factor (NGF) secreted in culture by L cells have been studied by sedimentation and gel filtration chromatography. Results indicate that L cell NGF has a molecular weight of 160,000. It contains as part of its structure a protein component that is biologically, immun...
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.74.4.1492
更新日期:1977-04-01 00:00:00
abstract::Remembering is a complex process that involves recalling specific details, such as who you were with when you celebrated your last birthday, as well as contextual information, such as the place where you celebrated. It is well established that the act of remembering enhances long-term retention of the retrieved inform...
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.1800006115
更新日期:2018-10-23 00:00:00
abstract::In phylogenetic reconstruction, two types of bacterial tyrosyl-tRNA synthetases (TyrRS) form distinct clades with many bacterial phyla represented in both clades. Very few taxa possess both forms, and maximum likelihood analysis of the distribution of TyrRS types suggests horizontal gene transfer (HGT), rather than an...
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.1001418107
更新日期:2010-06-08 00:00:00
abstract::The 16S rRNA genes of Pyrobaculum aerophilum and Pyrobaculum islandicum were amplified by the polymerase chain reaction, and the resulting products were sequenced directly. The two organisms are closely related by this measure (over 98% similar). However, they differ in that the (lone) 16S rRNA gene of Pyrobaculum aer...
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.90.6.2547
更新日期:1993-03-15 00:00:00