An artificial cell-cycle inhibitor isolated from a combinatorial library.

Abstract:

:Understanding the genetic networks that operate inside cells will require the dissection of interactions among network members. Here we describe a peptide aptamer isolated from a combinatorial library that distinguishes among such interactions. This aptamer binds to cyclin-dependent kinase 2 (Cdk2) and inhibits its kinase activity. In contrast to naturally occurring inhibitors, such as p21(Cip1), which inhibit the activity of Cdk2 on all its substrates, inhibition by pep8 has distinct substrate specificity. We show that the aptamer binds to Cdk2 at or near its active site and that its mode of inhibition is competitive. Expression of pep8 in human cells retards their progression through the G1 phase of the cell cycle. Our results suggest that the aptamer inhibits cell-cycle progression by blocking the activity of Cdk2 on substrates needed for the G1-to-S transition. This work demonstrates the feasibility of selection of artificial proteins to perform functions not developed during evolution. The ability to select proteins that block interactions between a gene product and some partners but not others should make sophisticated genetic manipulations possible in human cells and other currently intractable systems.

authors

Cohen BA,Colas P,Brent R

doi

10.1073/pnas.95.24.14272

subject

Has Abstract

pub_date

1998-11-24 00:00:00

pages

14272-7

issue

24

eissn

0027-8424

issn

1091-6490

journal_volume

95

pub_type

杂志文章
  • Vitamin D-mediated modifications in protein-DNA interactions at two promoter elements of the osteocalcin gene.

    abstract::By the combined use of DNase I footprinting, electrophoretic mobility-shift assay, and methylation interference analysis, we have identified a series of sequence-specific protein-DNA interactions in the 5' flanking region of the rat osteocalcin gene. Stimulation of osteocalcin gene expression by 1,25-dihydroxyvitamin ...

    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.87.5.1701

    authors: Markose ER,Stein JL,Stein GS,Lian JB

    更新日期:1990-03-01 00:00:00

  • Identification of cation-binding sites on actin that drive polymerization and modulate bending stiffness.

    abstract::The assembly of actin monomers into filaments and networks plays vital roles throughout eukaryotic biology, including intracellular transport, cell motility, cell division, determining cellular shape, and providing cells with mechanical strength. The regulation of actin assembly and modulation of filament mechanical p...

    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.1211078109

    authors: Kang H,Bradley MJ,McCullough BR,Pierre A,Grintsevich EE,Reisler E,De La Cruz EM

    更新日期:2012-10-16 00:00:00

  • Mosquito RUNX4 in the immune regulation of PPO gene expression and its effect on avian malaria parasite infection.

    abstract::Prophenoloxidases (PPOs) are key enzymes of the melanization reaction, which is a prominent defense mechanism of arthropods. The mosquito Aedes aegypti has ten PPO genes in the genome, four of which (PPO1, PPO3, PPO5, and PPO8) were expressed in response to microbial infection. Cactus depletion resulted in transcripti...

    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.0804658105

    authors: Zou Z,Shin SW,Alvarez KS,Bian G,Kokoza V,Raikhel AS

    更新日期:2008-11-25 00:00:00

  • Molecular determinants of tissue selectivity in estrogen receptor modulators.

    abstract::Interaction of the estrogen receptor/ligand complex with a DNA estrogen response element is known to regulate gene transcription. In turn, specific conformations of the receptor-ligand complex have been postulated to influence unique subsets of estrogen-responsive genes resulting in differential modulation and, ultima...

    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.94.25.14105

    authors: Grese TA,Sluka JP,Bryant HU,Cullinan GJ,Glasebrook AL,Jones CD,Matsumoto K,Palkowitz AD,Sato M,Termine JD,Winter MA,Yang NN,Dodge JA

    更新日期:1997-12-09 00:00:00

  • Induction of DNA synthesis in terminally differentiated myotubes by the activation of the src gene of Rous sarcoma virus.

    abstract::Mononucleated myogenic cells from 11-day-old chicken embryos were infected with tsLA24 or tsNY68, temperature-sensitive transformation mutants of Rous sarcoma virus. The infected mononucleated myogenic cells were incubated at the nonpermissive temperature (41 degrees C) and allowed to develop into multinucleated myotu...

    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.75.11.5501

    authors: Kobayashi N,Kaji A

    更新日期:1978-11-01 00:00:00

  • Shear stress-dependent regulation of apical endocytosis in renal proximal tubule cells mediated by primary cilia.

    abstract::The kidney has an extraordinary ability to maintain stable fractional solute and fluid reabsorption over a wide range of glomerular filtration rates (GFRs). Internalization of filtered low molecular weight proteins, vitamins, hormones, and other small molecules is mediated by the proximal tubule (PT) multiligand recep...

    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.1402195111

    authors: Raghavan V,Rbaibi Y,Pastor-Soler NM,Carattino MD,Weisz OA

    更新日期:2014-06-10 00:00:00

  • JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age.

    abstract::Chronic, low grade, sterile inflammation frequently accompanies aging and age-related diseases. Cellular senescence is associated with the production of proinflammatory chemokines, cytokines, and extracellular matrix (ECM) remodeling proteases, which comprise the senescence-associated secretory phenotype (SASP). We 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.1515386112

    authors: Xu M,Tchkonia T,Ding H,Ogrodnik M,Lubbers ER,Pirtskhalava T,White TA,Johnson KO,Stout MB,Mezera V,Giorgadze N,Jensen MD,LeBrasseur NK,Kirkland JL

    更新日期:2015-11-17 00:00:00

  • Genetic requirements for mycobacterial survival during infection.

    abstract::Despite the importance of tuberculosis as a public health problem, we know relatively little about the molecular mechanisms used by the causative organism, Mycobacterium tuberculosis, to persist in the host. To define these mechanisms, we have mutated virtually every nonessential gene of M. tuberculosis and determined...

    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.2134250100

    authors: Sassetti CM,Rubin EJ

    更新日期:2003-10-28 00:00:00

  • Deconstruction of biomass enabled by local demixing of cosolvents at cellulose and lignin surfaces.

    abstract::A particularly promising approach to deconstructing and fractionating lignocellulosic biomass to produce green renewable fuels and high-value chemicals pretreats the biomass with organic solvents in aqueous solution. Here, neutron scattering and molecular-dynamics simulations reveal the temperature-dependent morpholog...

    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.1922883117

    authors: Pingali SV,Smith MD,Liu SH,Rawal TB,Pu Y,Shah R,Evans BR,Urban VS,Davison BH,Cai CM,Ragauskas AJ,O'Neill HM,Smith JC,Petridis L

    更新日期:2020-07-21 00:00:00

  • Pericentromeric satellite repeat expansions through RNA-derived DNA intermediates in cancer.

    abstract::Aberrant transcription of the pericentromeric human satellite II (HSATII) repeat is present in a wide variety of epithelial cancers. In deriving experimental systems to study its deregulation, we observed that HSATII expression is induced in colon cancer cells cultured as xenografts or under nonadherent conditions in ...

    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.1518008112

    authors: Bersani F,Lee E,Kharchenko PV,Xu AW,Liu M,Xega K,MacKenzie OC,Brannigan BW,Wittner BS,Jung H,Ramaswamy S,Park PJ,Maheswaran S,Ting DT,Haber DA

    更新日期:2015-12-08 00:00:00

  • The protein ENH is a cytoplasmic sequestration factor for Id2 in normal and tumor cells from the nervous system.

    abstract::Id2 is a natural inhibitor of the basic helix-loop-helix transcription factors and the retinoblastoma tumor suppressor protein. Active Id2 prevents differentiation and promotes cell-cycle progression and tumorigenesis in the nervous system. A key event that regulates Id2 activity during differentiation is translocatio...

    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.0600168103

    authors: Lasorella A,Iavarone A

    更新日期:2006-03-28 00:00:00

  • In vitro expression in eukaryotic cells of a prion protein gene cloned from scrapie-infected mouse brain.

    abstract::It has been proposed that the causative agent of scrapie represents a class of infectious particle that is devoid of nucleic acid and that an altered form of the endogenous prion protein (PrP) is the agent. However, it has been difficult to exclude the possibility that PrP purified from scrapie tissues might be contam...

    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.85.13.4657

    authors: Caughey B,Race RE,Vogel M,Buchmeier MJ,Chesebro B

    更新日期:1988-07-01 00:00:00

  • CYCLOPS reveals human transcriptional rhythms in health and disease.

    abstract::Circadian rhythms modulate many aspects of physiology. Knowledge of the molecular basis of these rhythms has exploded in the last 20 years. However, most of these data are from model organisms, and translation to clinical practice has been limited. Here, we present an approach to identify molecular rhythms in humans f...

    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.1619320114

    authors: Anafi RC,Francey LJ,Hogenesch JB,Kim J

    更新日期:2017-05-16 00:00:00

  • Small RNA profiling in Mycobacterium tuberculosis identifies MrsI as necessary for an anticipatory iron sparing response.

    abstract::One key to the success of Mycobacterium tuberculosis as a pathogen is its ability to reside in the hostile environment of the human macrophage. Bacteria adapt to stress through a variety of mechanisms, including the use of small regulatory RNAs (sRNAs), which posttranscriptionally regulate bacterial gene expression. H...

    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.1718003115

    authors: Gerrick ER,Barbier T,Chase MR,Xu R,François J,Lin VH,Szucs MJ,Rock JM,Ahmad R,Tjaden B,Livny J,Fortune SM

    更新日期:2018-06-19 00:00:00

  • Cloning of the cDNA for the human beta 1-adrenergic receptor.

    abstract::Screening of a human placenta lambda gt11 library has led to the isolation of the cDNA for the human beta 1-adrenergic receptor (beta 1AR). Used as the probe was the human genomic clone termed G-21. This clone, which contains an intronless gene for a putative receptor, was previously isolated by virtue of its cross hy...

    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.84.22.7920

    authors: Frielle T,Collins S,Daniel KW,Caron MG,Lefkowitz RJ,Kobilka BK

    更新日期:1987-11-01 00:00:00

  • Nucleic acid-binding polymers as anti-inflammatory agents.

    abstract::Dead and dying cells release nucleic acids. These extracellular RNAs and DNAs can be taken up by inflammatory cells and activate multiple nucleic acid-sensing toll-like receptors (TLR3, 7, 8, and 9). The inappropriate activation of these TLRs can engender a variety of inflammatory and autoimmune diseases. The redundan...

    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.1105777108

    authors: Lee J,Sohn JW,Zhang Y,Leong KW,Pisetsky D,Sullenger BA

    更新日期:2011-08-23 00:00:00

  • Tissue-specific regulation of bovine heart cytochrome-c oxidase activity by ADP via interaction with subunit VIa.

    abstract::The activity of reconstituted cytochrome-c oxidase (EC 1.9.3.1) from bovine heart is stimulated by intraliposomal ADP but not by NaCl of the same ionic strength. A monoclonal antibody which reacts with subunits VIa-H (heart-type) and VIc, due to the evolutionary relationship between these subunits, also stimulates the...

    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.90.5.1652

    authors: Anthony G,Reimann A,Kadenbach B

    更新日期:1993-03-01 00:00:00

  • Surface charge of polyoxometalates modulates polymerization of the scrapie prion protein.

    abstract::Prions are composed solely of an alternatively folded isoform of the prion protein (PrP), designated PrP(Sc). N-terminally truncated PrP(Sc), denoted PrP 27-30, retains infectivity and polymerizes into rods with the ultrastructural and tinctorial properties of amyloid. We report here that some polyoxometalates (POMs) ...

    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.0812770106

    authors: Wille H,Shanmugam M,Murugesu M,Ollesch J,Stubbs G,Long JR,Safar JG,Prusiner SB

    更新日期:2009-03-10 00:00:00

  • Quantitative MS-based enzymology of caspases reveals distinct protein substrate specificities, hierarchies, and cellular roles.

    abstract::Proteases constitute the largest enzyme family, yet their biological roles are obscured by our rudimentary understanding of their cellular substrates. There are 12 human caspases that play crucial roles in inflammation and cell differentiation and drive the terminal stages of cell death. Recent N-terminomics technolog...

    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.1524900113

    authors: Julien O,Zhuang M,Wiita AP,O'Donoghue AJ,Knudsen GM,Craik CS,Wells JA

    更新日期:2016-04-05 00:00:00

  • Primer retention owing to the absence of RNase H1 is catastrophic for mitochondrial DNA replication.

    abstract::Encoding ribonuclease H1 (RNase H1) degrades RNA hybridized to DNA, and its function is essential for mitochondrial DNA maintenance in the developing mouse. Here we define the role of RNase H1 in mitochondrial DNA replication. Analysis of replicating mitochondrial DNA in embryonic fibroblasts lacking RNase H1 reveals ...

    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.1503653112

    authors: Holmes JB,Akman G,Wood SR,Sakhuja K,Cerritelli SM,Moss C,Bowmaker MR,Jacobs HT,Crouch RJ,Holt IJ

    更新日期:2015-07-28 00:00:00

  • Scale-invariant structure of strongly conserved sequence in genomic intersections and alignments.

    abstract::A power-law distribution of the length of perfectly conserved sequence from mouse/human whole-genome intersection and alignment is exhibited. Spatial correlations of these elements within the mouse genome are studied. It is argued that these power-law distributions and correlations are comprised in part by functional ...

    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.0605735103

    authors: Salerno W,Havlak P,Miller J

    更新日期:2006-08-29 00:00:00

  • Oil platforms off California are among the most productive marine fish habitats globally.

    abstract::Secondary (i.e., heterotrophic or animal) production is a main pathway of energy flow through an ecosystem as it makes energy available to consumers, including humans. Its estimation can play a valuable role in the examination of linkages between ecosystem functions and services. We found that oil and gas platforms 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.1411477111

    authors: Claisse JT,Pondella DJ 2nd,Love M,Zahn LA,Williams CM,Williams JP,Bull AS

    更新日期:2014-10-28 00:00:00

  • Dynamic interplay between nitration and phosphorylation of tubulin cofactor B in the control of microtubule dynamics.

    abstract::Tubulin cofactor B (TCoB) plays an important role in microtubule dynamics by facilitating the dimerization of alpha- and beta-tubulin. Recent evidence suggests that p21-activated kinase 1 (Pak1), a major signaling nodule in eukaryotic cells, phosphorylates TCoB on Ser-65 and Ser-128 and plays an essential role in micr...

    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.0705149104

    authors: Rayala SK,Martin E,Sharina IG,Molli PR,Wang X,Jacobson R,Murad F,Kumar R

    更新日期:2007-12-04 00:00:00

  • Transgenic study of parallelism in plant morphological evolution.

    abstract::Developmental constraint is indicated when one finds that similar genetic mechanisms are responsible for independent origins of the same derived phenotype. We studied three independent origins of rosette flowering within the mustard family and attempted to evaluate the extent to which the same mechanisms were involved...

    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.0401824101

    authors: Yoon HS,Baum DA

    更新日期:2004-04-27 00:00:00

  • Quantitative dissection of hydrogen bond-mediated proton transfer in the ketosteroid isomerase active site.

    abstract::Hydrogen bond networks are key elements of protein structure and function but have been challenging to study within the complex protein environment. We have carried out in-depth interrogations of the proton transfer equilibrium within a hydrogen bond network formed to bound phenols in the active site of ketosteroid is...

    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.1302191110

    authors: Sigala PA,Fafarman AT,Schwans JP,Fried SD,Fenn TD,Caaveiro JM,Pybus B,Ringe D,Petsko GA,Boxer SG,Herschlag D

    更新日期:2013-07-09 00:00:00

  • Synaptic mechanisms of persistent reverberatory activity in neuronal networks.

    abstract::For brain functions such as working memory and motor planning, neuronal circuits are able to sustain persistent activity after transient inputs. Theoretical studies have suggested that persistent activity can exist in recurrently connected networks as active reverberation. However, the actual cellular processes underl...

    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.0500717102

    authors: Lau PM,Bi GQ

    更新日期:2005-07-19 00:00:00

  • Lipid monolayer image dipoles.

    abstract::A simple model is described for calculating the electrostatic energy of lipid domains at the air-water interface, taking account of dipole-dipole repulsions between the lipid molecules themselves, as well as interactions between the molecular dipoles and image dipoles in the subphase. The model assumes that the molecu...

    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.92.19.8823

    authors: McConnell HM,Bazaliy YB

    更新日期:1995-09-12 00:00:00

  • Identifying the subproteome of kinetically stable proteins via diagonal 2D SDS/PAGE.

    abstract::Most proteins are in equilibrium with partially and globally unfolded conformations. In contrast, kinetically stable proteins (KSPs) are trapped by an energy barrier in a specific state, unable to transiently sample other conformations. Among many potential roles, it appears that kinetic stability (KS) is a feature us...

    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.0705417104

    authors: Xia K,Manning M,Hesham H,Lin Q,Bystroff C,Colón W

    更新日期:2007-10-30 00:00:00

  • Transloading of tumor antigen-derived peptides into antigen-presenting cells.

    abstract::The discovery of a steadily growing number of tumor antigens (TAs) has made generic, cell-free, peptide-based cancer vaccines a possible alternative to cytokine-transfected autologous cellular cancer vaccines. The major drawback of peptide vaccines, however, is the poor immunogenicity of peptides. It is commonly thoug...

    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.94.7.3256

    authors: Buschle M,Schmidt W,Zauner W,Mechtler K,Trska B,Kirlappos H,Birnstiel ML

    更新日期:1997-04-01 00:00:00

  • Major species differences between humans and rodents in the susceptibility to pancreatic beta-cell injury.

    abstract::The ability of beta cells to endure assaults may be relevant in the development of insulin-dependent diabetes mellitus. This study examines the susceptibility of human pancreatic islets to agents that are cytotoxic for rodent beta cells--i.e., sodium nitroprusside (NP, a nitric oxide donor), streptozotocin (SZ), or al...

    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.91.20.9253

    authors: Eizirik DL,Pipeleers DG,Ling Z,Welsh N,Hellerström C,Andersson A

    更新日期:1994-09-27 00:00:00