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a comprehensive functional analysis of pten mutations: implications in tumor- and autism-related syndromes.the pten (phosphatase and tensin homolog) phosphatase is unique in mammals in terms of its tumor suppressor activity, exerted by dephosphorylation of the lipid second messenger pip(3) (phosphatidylinositol 3,4,5-trisphosphate), which activates the phosphoinositide 3-kinase/akt/mtor (mammalian target of rapamycin) oncogenic pathway. loss-of-function mutations in the pten gene are frequent in human cancer and in the germline of patients with pten hamartoma tumor-related syndromes (phtss). in addit ...201121828076
interaction between nucleosome assembly protein 1-like family members.mammals possess five nucleosome assembly protein 1-like (nap1l) proteins, with three of them being expressed exclusively in the nervous system. the biological importance of the neuron-specific nap1l2 protein is demonstrated by the neural tube defects occurring during the embryonic development of nap1l2 mutant mice, which are associated with an overproliferation of neural stem cells and decreased neuronal differentiation. nap1l2 controls the expression of its target genes, such as the cell cycle ...201121333655
distinct regulation of p53-mediated apoptosis by protein kinase ca, d, e and ?: evidence in yeast for transcription-dependent and -independent p53 apoptotic mechanisms.the role of individual protein kinase c (pkc) isoforms in the regulation of p53-mediated apoptosis is still uncertain. using yeast cells co-expressing the human wild-type p53 and a single mammalian pkca, d, e or ?, we showed a differential regulation of p53-mediated apoptosis by these pkc isoforms. whereas pkca and ? had no effect on p53 activity, pkcd and e stimulated a p53-mediated mitochondria-dependent apoptosis. moreover, using pifithrin-a and -µ, selective inhibitors of p53 transcriptional ...201121338602
development of chromanes as novel inhibitors of the uncoupling proteins.the uncoupling proteins (ucps) are mitochondrial carriers that modulate the energetic efficiency and, as a result, can lower superoxide levels. here, we describe the discovery of a small-molecule inhibitor of the ucps. screening of potential ucp1 regulators led to the identification of chromane derivatives that inhibit its proton conductance. members of the ucp family can act as a defense against oxidative stress and, thus, ucp2 plays a protective role in tumor cells. high ucp2 levels have been ...201121338923
xenotransplantation of mitochondrial electron transfer enzyme, ndi1, in myocardial reperfusion injury.a significant consequence of ischemia/reperfusion (i/r) is mitochondrial respiratory dysfunction, leading to energetic deficits and cellular toxicity from reactive oxygen species (ros). mammalian complex i, a nadh-quinone oxidoreductase enzyme, is a multiple subunit enzyme that oxidizes nadh and pumps protons across the inner membrane. damage to complex i leads to superoxide production which further damages complex i as well as other proteins, lipids and mtdna. the yeast, s. cerevisiae, expresse ...201121339825
membrane-associated ubiquitin ligase complex containing gp78 mediates sterol-accelerated degradation of 3-hydroxy-3-methylglutaryl-coenzyme a reductase.the endoplasmic reticulum (er)-associated degradation (erad) pathway in the yeast saccharomyces cerevisiae is mediated by two membrane-bound ubiquitin ligases, doa10 and hrd1. these enzymes are found in distinct multiprotein complexes that allow them to recognize and target a variety of substrates for proteasomal degradation. although multiprotein complexes containing mammalian erad ubiquitin ligases likely exist, they have yet to be identified and characterized in detail. here, we identify two ...201121343306
hzwint-1 bridges the inner and outer kinetochore: identification of the kinetochore localization domain and the hzw10-interaction domain.accurate chromosome segregation in mitosis is required to maintain genetic stability. hzwint-1 [human zw10 (zeste white 10)-interacting protein 1] is a kinetochore protein known to interact with the kinetochore checkpoint protein hzw10. hzw10, along with its partners rod (roughdeal) and hzwilch, form a complex which recruits dynein-dynactin and mad1-mad2 complexes to the kinetochore and are essential components of the mitotic checkpoint. hzwint-1 localizes to the kinetochore in prophase, before ...201121345172
pharmacokinetic-pharmacodynamic modeling of the inhibitory effects of naproxen on the time-courses of inflammatory pain, fever, and the ex vivo synthesis of txb2 and pge2 in rats.to quantify and compare the time-course and potency of the analgesic and antipyretic effects of naproxen in conjunction with the inhibition of pge(2) and txb(2).201121347567
phosphate-responsive signaling pathway is a novel component of nad+ metabolism in saccharomyces cerevisiae.nicotinamide adenine dinucleotide (nad(+)) is an essential cofactor involved in various cellular biochemical reactions. to date the signaling pathways that regulate nad(+) metabolism remain unclear due to the dynamic nature and complexity of the nad(+) metabolic pathways and the difficulty of determining the levels of the interconvertible pyridine nucleotides. nicotinamide riboside (nmr) is a key pyridine metabolite that is excreted and re-assimilated by yeast and plays important roles in the ma ...201121349851
importin α/β mediates nuclear import of individual sumo e1 subunits and of the holo-enzyme.sumoylation, reversible attachment of small ubiquitin-related modifier (sumo), serves to regulate hundreds of proteins. consistent with predominantly nuclear targets, enzymes required for attachment and removal of sumo are highly enriched in this compartment. this is true also for the first enzyme of the sumoylation cascade, the sumo e1 enzyme heterodimer, aos1/uba2 (sae1/sae2). this essential enzyme serves to activate sumo and to transfer it to the e2-conjugating enzyme ubc9. although the last ...201121209321
role of the ubiquitin-like protein urm1 as a noncanonical lysine-directed protein modifier.the ubiquitin (ub)-related modifier urm1 functions as a sulfur carrier in trna thiolation by means of a mechanism that requires the formation of a thiocarboxylate at the c-terminal glycine residue of urm1. however, whether urm1 plays an additional role as a ub-like protein modifier remains unclear. here, we show that urm1 is conjugated to lysine residues of target proteins and that oxidative stress enhances protein urmylation in both saccharomyces cerevisiae and mammalian cells. similar to ubiqu ...201121209336
ubiquitin-dependent proteasomal degradation of human liver cytochrome p450 2e1: identification of sites targeted for phosphorylation and ubiquitination.human liver cyp2e1 is a monotopic, endoplasmic reticulum-anchored cytochrome p450 responsible for the biotransformation of clinically relevant drugs, low molecular weight xenobiotics, carcinogens, and endogenous ketones. cyp2e1 substrate complexation converts it into a stable slow-turnover species degraded largely via autophagic lysosomal degradation. substrate decomplexation/withdrawal results in a fast turnover cyp2e1 species, putatively generated through its futile oxidative cycling, that inc ...201121209460
mutation to bax beyond the bh3 domain disrupts interactions with pro-survival proteins and promotes apoptosis.pro-survival members of the bcl-2 family of proteins restrain the pro-apoptotic activity of bax, either directly through interactions with bax or indirectly by sequestration of activator bh3-only proteins, or both. mutations in bax that promote apoptosis can provide insight into how bax is regulated. here, we describe crystal structures of the pro-survival proteins mcl-1 and bcl-x(l) in complex with a 34-mer peptide from bax that encompasses its bh3 domain. these structures reveal canonical inte ...201121199865
single-cell tracking with a reversing flow cytometer.we have developed an instrument based on a flow cytometer platform that is capable of tracking individual, suspended cells over extended time periods. the instrument repeatedly moves in a capillary the same volume segment of fluid containing tens to hundreds of suspended cells through the focal point of a laser. individual cells are then tracked based on the timing of when they cross the laser, and cell properties are measured as in a conventional flow cytometer. because cells are repeatedly mea ...201121182184
role of the interface between the fmn and fad domains in the control of redox potential and electronic transfer of nadph-cytochrome p450 reductase.cpr (nadph-cytochrome p450 reductase) is a multidomain protein containing two flavin-containing domains joined by a connecting domain thought to control the necessary movements of the catalytic domains during electronic cycles. we present a detailed biochemical analysis of two chimaeric cprs composed of the association of human or yeast fmn with the alternative connecting/fad domains. despite the assembly of domains having a relatively large evolutionary distance between them, our data support t ...201121265736
surface display of human lactoferrin using a glycosylphosphatidylinositol-anchored protein of saccharomyces cerevisiae in pichia pastoris.a cell surface display system was developed in pichia pastoris using the gene tip1, encoding the glycosylphosphatidylinositol (gpi)-anchored protein of saccharomyces cerevisiae (sctip). human lactoferrin cdna (hlf) was fused to a full-length tip1 dna (sctip ( 630 )) or a short-tip1 fragment (sctip ( 120 )) encoding the 40 c-terminal amino acids of sctip. both hlf-sctip fusion genes were expressed in p. pastoris smd 1168. the fused protein was detected by western blotting after extraction of the ...201121267758
rad52 function prevents chromosome loss and truncation in candida albicans.rad52 is required for almost all recombination events in saccharomyces cerevisiae. we took advantage of the heterozygosity of his4 in the candida albicans sc5314 lineage to study the role of rad52 in the genomic stability of this important fungal pathogen. the rate of loss of heterozygosity (loh) at his4 in rad52-?? strains was ~10(-3) , at least 100-fold higher than in rad52(+) strains. loh of whole chromosome 4 or truncation of the homologue that carries the functional his4 allele was detected ...201121272099
dissection of the relative contribution of the schizosaccharomyces pombe ctr4 and ctr5 proteins to the copper transport and cell surface delivery functions.the ctr1 family of proteins mediates high-affinity copper (cu) acquisition in eukaryotic organisms. in the fission yeast schizosaccharomyces pombe, cu uptake is carried out by a heteromeric complex formed by the ctr4 and ctr5 proteins. unlike human and saccharomyces cerevisiae ctr1 proteins, ctr4 and ctr5 are unable to function independently in cu acquisition. instead, both proteins physically interact with each other to form a ctr4-ctr5 heteromeric complex, and are interdependent for secretion ...201121273250
cell biology. why starving cells eat themselves. 201121273476
saccharomyces cerevisiae gis2 interacts with the translation machinery and is orthogonal to myotonic dystrophy type 2 protein znf9.the myotonic dystrophy type 2 protein znf9/cnbp is a small nucleic acid binding protein proposed to act as a regulator of transcription and translation. the precise functions and activity of this protein are poorly understood. previous studies suggested that znf9 regulates translation and facilitates the process of cap-independent translation through interactions with mrna and the translating ribosome. to help determine the role played by znf9 in the activation of translation initiation, we comb ...201121277287
preparation of cho cell-derived rhifn-?-fc with improved pharmacokinetics.interferon-omega (ifn-?) may be a useful, promising and alternative antiviral agent, in addition to ifn-a-2a and ifn-a-2b. to improve the pharmacokinetics of ifn-? for clinical use, the recombinant human ifn-?-fc fusion protein (rhifn-?-fc) was expressed in a chinese hamster ovary cell line (cho-s), due to the longer serum half-life of rhifn-?-fc compared to the native ifn-? protein, and purified by affinity chromatography. physicochemical characterization of the purified fusion protein was perf ...201121277904
tyrosine 656 in topoisomerase iiß is important for the catalytic activity of the enzyme: identification based on artifactual +80-da modification at this site.topoisomerase (topo) ii catalyzes topological changes in dna. although both human isozymes, topo iia and ß are phosphorylated, site-specific phosphorylation of topo iiß is poorly characterized. using lc-ms/ms analysis of topo iiß, cleaved with trypsin, arg c or cyanogen bromide (cnbr) plus trypsin, we detected four +80-da modified sites: tyr656, ser1395, thr1426 and ser1545. phosphorylation at ser1395, thr1426 and ser1545 was established based on neutral loss of h(3) po(4) (-98?da) in the cid sp ...201121280220
cellular functions of ufd2 and ufd3 in proteasomal protein degradation depend on cdc48 binding.the chaperone-related aaa atpase cdc48 (p97/vcp in higher eukaryotes) segregates ubiquitylated proteins for subsequent degradation by the 26s proteasome or for nonproteolytic fates. the specific outcome of cdc48 activity is controlled by the evolutionary conserved cofactors ufd2 and ufd3, which antagonistically regulate the substrates' ubiquitylation states. in contrast to the interaction of ufd3 and cdc48, the interaction between the ubiquitin chain elongating enzyme ufd2 and cdc48 has not been ...201121282470
expansions, contractions, and fragility of the spinocerebellar ataxia type 10 pentanucleotide repeat in yeast.spinocerebellar ataxia 10 (sca10) is an autosomal dominant disease caused by large-scale expansions of the (attct)(n) repeat within an intron of the human atxn10 gene. in contrast to other expandable repeats, this pentanucleotide repeat does not form stable intra- or interstranded dna structures, being a dna unwinding element instead. we analyzed the instability of the (attct)(n) repeat in a yeast experimental system, where its expansions led to inactivation of the ura3 reporter gene. the inacti ...201121282659
cryptococcal osteomyelitis of the skull.an otherwise healthy 65-year-old male from a rural area presented with a 1-month old non-tender scalp mass. he had a history of being stuck with a stone in the parietal region a year earlier but hadn't developed any complications. needle aspiration of the mass revealed numerous yeast cells, which were confirmed to be cryptoccus neoformans. this case describes a rare presentation of c. neoformans infection in a human immunodeficiency virus (hiv)-negative patient. moreover, while osteomyelitis due ...201121284568
zinc-finger protein 90 negatively regulates neuron-restrictive silencer factor-mediated transcriptional repression of fetal cardiac genes.neuron-restrictive silencer factor (nrsf) is a zinc-finger transcription factor that binds to specific dna sequences (nrse) to repress transcription. by down-regulating the transcription of its target genes, nrsf contributes to the regulation of various biological processes, including neuronal differentiation, carcinogenesis and cardiovascular homeostasis. we previously reported that nrsf regulates expression of the cardiac fetal gene program, and that attenuation of nrsf-mediated repression con ...201121284946
allele-specific effects of thoracic aortic aneurysm and dissection alpha-smooth muscle actin mutations on actin function.twenty-two missense mutations in acta2, which encodes a-smooth muscle actin, have been identified to cause thoracic aortic aneurysm and dissection. limited access to diseased tissue, the presence of multiple unresolvable actin isoforms in the cell, and lack of an animal model have prevented analysis of the biochemical mechanisms underlying this pathology. we have utilized actin from the yeast saccharomyces cerevisiae, 86% identical to human a-smooth muscle actin, as a model. two of the known hum ...201121288906
nutrient stress does not cause retrograde transport of cytoplasmic trna to the nucleus in evolutionarily diverse organisms.intracellular trafficking of trna was long thought to be a one-way trip from the site of biogenesis in the nucleus to the translation machinery in the cytoplasm. this view has recently been challenged, however, by the discovery that trna can move retrograde from the cytoplasm back to the nucleus in saccharomyces cerevisiae and rat hepatoma h4iie cells during nutrient stress and in s. cerevisiae after intron-containing pre-trnas are spliced in the cytoplasm. contrary to studies reported, we prese ...201121289100
the incorporation of 5-fluorouracil into rna affects the ribonucleolytic activity of the exosome subunit rrp6.5-fluorouracil (5fu) is a fluoropyrimidine used for the treatment of solid tumors. 5fu is a precursor of dttp and utp during biogenesis, and it interferes with both dna and rna metabolism. the rna exosome, a multisubunit complex with ribonucleolytic activity, has been identified as one of the targets of 5fu in yeast. studies in human cells have shown that the catalytic subunit of the nuclear exosome, rrp6, is specifically targeted. here, we have investigated the direct effect of 5fu on the activ ...201121289297
resilience of protein-protein interaction networks as determined by their large-scale topological features.the relationship between the structure and function of biological networks constitutes a fundamental issue in systems biology. particularly, the structure of protein-protein interaction networks is related to important biological functions. in this work, we investigated how such a resilience is determined by the large scale features of the respective networks. four species are taken into account, namely yeast saccharomyces cerevisiae, worm caenorhabditis elegans, fly drosophila melanogaster and ...201121298132
simulating and validating proteomics data and search results.the computational simulation of complete proteomic data sets and their utility to validate detection and interpretation algorithms, to aid in the design of experiments and to assess protein and peptide false discovery rates is presented. the simulation software has been developed for emulating data originating from data-dependent and data-independent lc-ms workflows. data from all types of commonly used hybrid mass spectrometers can be simulated. the algorithms are based on empirically derived p ...201121298790
psm3 acetylation on conserved lysine residues is dispensable for viability in fission yeast but contributes to eso1-mediated sister chromatid cohesion by antagonizing wpl1.in budding yeast and humans, cohesion establishment during s phase requires the acetyltransferase eco1/esco1-2, which acetylates the cohesin subunit smc3 on two conserved lysine residues. whether smc3 is the sole eco1/esco1-2 effector and how smc3 acetylation promotes cohesion are unknown. in fission yeast (schizosaccharomyces pombe), as in humans, cohesin binding to g(1) chromosomes is dynamic and the unloading reaction is stimulated by wpl1 (human ortholog, wapl). during s phase, a subpopulati ...201121300781
subunit organization of the human ino80 chromatin remodeling complex: an evolutionarily conserved core complex catalyzes atp-dependent nucleosome remodeling.we previously identified and purified a human atp-dependent chromatin remodeling complex with similarity to the saccharomyces cerevisiae ino80 complex (jin, j., cai, y., yao, t., gottschalk, a. j., florens, l., swanson, s. k., gutierrez, j. l., coleman, m. k., workman, j. l., mushegian, a., washburn, m. p., conaway, r. c., and conaway, j. w. (2005) j. biol. chem. 280, 41207-41212) and demonstrated that it is composed of (i) a snf2 family atpase (hino80) related in sequence to the s. cerevisiae i ...201121303910
accurate quantification of functional analogy among close homologs.correctly evaluating functional similarities among homologous proteins is necessary for accurate transfer of experimental knowledge from one organism to another, and is of particular importance for the development of animal models of human disease. while the fact that sequence similarity implies functional similarity is a fundamental paradigm of molecular biology, sequence comparison does not directly assess the extent to which two proteins participate in the same biological processes, and has l ...201121304936
requirement for acetyl-coa carboxylase in trypanosoma brucei is dependent upon the growth environment.trypanosoma brucei, the causative agent of human african trypanosomiasis, possesses two fatty acid synthesis pathways: a major de novo synthesis pathway in the er and a mitochondrial pathway. the 2-carbon donor for both pathways is malonyl-coa, which is synthesized from acetyl-coa by acetyl-coa carboxylase (acc). here, we show that t. brucei acc shares the same enzyme architecture and moderate ~ 30% identity with yeast and human accs. acc is cytoplasmic and appears to be distributed throughout t ...201121306439
saccharomyces cerevisiae as a model organism: a comparative study.model organisms are used for research because they provide a framework on which to develop and optimize methods that facilitate and standardize analysis. such organisms should be representative of the living beings for which they are to serve as proxy. however, in practice, a model organism is often selected ad hoc, and without considering its representativeness, because a systematic and rational method to include this consideration in the selection process is still lacking.201121311596
rho gtpase cdc42 is a direct interacting partner of adenomatous polyposis coli protein and can alter its cellular localization.adenomatous polyposis coli (apc) is a tumor suppressor gene product involved in colon cancer. apc is a large multidomain molecule of 2843 amino acid residues and connects cell-cell adhesion, the f-actin/microtubule cytoskeleton and the nucleus. here we show that cdc42 interacts directly with the first three armadillo repeats of apc by yeast two-hybrid screens. we confirm the cdc42-apc interaction using pulldown assays in vitro and fret assays in vivo. interestingly, cdc42 interacts with apc at l ...201121311754
synthesis and biological activity of splitomicin analogs targeted at human nad(+)-dependent histone deacetylases (sirtuins).small molecules interfering with posttranslational modification of histones are of interest as tools to study epigenetic regulation of gene transcription. specifically, drugs that interfere with histone deacetylation could be useful to induce differentiation, growth arrest as well as apoptotic cell death in tumor cells. one class of histone deacetylases is known as sirtuins some of which (saccharomyces cerevisiae sir2) are for example inhibited by the lactone splitomicin leading to telomeric sil ...201121315612
the essential role of fkbp38 in regulating phosphatase of regenerating liver 3 (prl-3) protein stability.the phosphatase of regenerating liver-3 (prl-3) is a member of protein tyrosine phosphatases and whose deregulation is implicated in tumorigenesis and metastasis of many cancers. however, the underlying mechanism by which prl-3 is regulated is not known. in this study, we identified the peptidyl prolyl cis/trans isomerase fk506-binding protein 38 (fkbp38) as an interacting protein of prl-3 using a yeast two-hybrid system. fkbp38 specifically binds to prl-3 in vivo, and that the n-terminal region ...201121320469
detecting protein-protein interactions in vesicular stomatitis virus using a cytoplasmic yeast two hybrid system.protein-protein interactions play an important role in many virus-encoded functions and in virus-host interactions. while a "classical" yeast two-hybrid system (y2h) is one of the most common techniques to detect such interactions, it has a number of limitations, including a requirement for the proteins of interest to be relocated to the nucleus. modified y2h, such as the sos recruitment system (srs), which detect interactions occurring in the cytoplasm rather than the nucleus, allow proteins fr ...201121320532
xenopus hjurp and condensin ii are required for cenp-a assembly.centromeric protein a (cenp-a) is the epigenetic mark of centromeres. cenp-a replenishment is necessary in each cell cycle to compensate for the dilution associated to dna replication, but how this is achieved mechanistically is largely unknown. we have developed an assay using xenopus egg extracts that can recapitulate the spatial and temporal specificity of cenp-a deposition observed in human cells, providing us with a robust in vitro system amenable to molecular dissection. here we show that ...201121321101
a generic system for the expression and purification of soluble and stable influenza neuraminidase.the influenza surface glycoprotein neuraminidase (na) is essential for the efficient spread of the virus. antiviral drugs such as tamiflu (oseltamivir) and relenza (zanamivir) that inhibit na enzyme activity have been shown to be effective in the treatment of influenza infections. the recent 'swine flu' pandemic and world-wide emergence of tamiflu-resistant seasonal human influenza a(h1n1) h(274)y have highlighted the need for the ongoing development of new anti-virals, efficient production of v ...201121326879
transcriptional and cellular responses to defective mitochondrial proteolysis in fission yeast.lon and m-aaa are the principal, regulated proteases required for protein maturation and turnover in the mitochondrial matrix of diverse species. to understand their roles in fission yeast (schizosaccharomyces pombe) mitochondria, we generated deletion strains lacking lon and m-aaa, individually (?lon1 and ?m-aaa) or together, ?lon1?m-aaa (?/?). all three strains were viable but incapable of respiratory growth on a non-fermentable carbon source due to mitochondrial dysfunction. confocal and elec ...201121354177
haploinsufficiency and the sex chromosomes from yeasts to humans.haploinsufficient (hi) genes are those for which a reduction in copy number in a diploid from two to one results in significantly reduced fitness. haploinsufficiency is increasingly implicated in human disease, and so predicting this phenotype could provide insights into the genetic mechanisms behind many human diseases, including some cancers.201121356089
identification and characterization of the mitochondrial rna polymerase and transcription factor in the fission yeast schizosaccharomyces pombe.we have characterized the mitochondrial transcription factor (mtf1) and rna polymerase (rpo41) of schizosaccharomyces pombe. deletion mutants show mtf1 or rpo41 to be essential for cell growth, cell morphology and mitochondrial membrane potential. overexpression of mtf1 and rpo41 can induce mitochondrial transcription. mtf1 and rpo41 can bind and transcribe mitochondrial promoters in vitro and the initiating nucleotides were the same in vivo and in vitro. mtf1 is required for efficient transcrip ...201121357609
elongator protein 3b negatively regulates ribosomal dna transcription in african trypanosomes.eukaryotic cells limit ribosomal dna (rdna) transcription by rna polymerase i (rnap-i) to maintain genome integrity. african trypanosomes present an excellent model for studies on rnap-i regulation because they possess a bifunctional rnap-i and because rnap-ii transcription appears unregulated. since elp3, the catalytic component of elongator, controls rnap-ii transcription in yeast and human cells, we predicted a role for a trypanosome elp3-related protein, elp3a or elp3b, in rnap-i regulation. ...201121357738
mutations in origin recognition complex gene orc4 cause meier-gorlin syndrome.meier-gorlin syndrome is a rare autosomal recessive genetic condition whose primary clinical hallmarks include small stature, small external ears and small or absent patellae. using marker-assisted mapping in multiple families from a founder population and traditional coding exon sequencing of positional candidate genes, we identified three different mutations in the gene encoding orc4, a component of the eukaryotic origin recognition complex, in five individuals with meier-gorlin syndrome. in t ...201121358631
the impact of the c-terminal domain on the interaction of human dna topoisomerase ii a and ß with dna.type ii dna topoisomerases are essential, ubiquitous enzymes that act to relieve topological problems arising in dna from normal cellular activity. their mechanism of action involves the atp-dependent transport of one dna duplex through a transient break in a second dna duplex; metal ions are essential for strand passage. humans have two isoforms, topoisomerase iia and topoisomerase iiß, that have distinct roles in the cell. the c-terminal domain has been linked to isoform specific differences i ...201121358820
selected reaction monitoring by linear ion-trap mass spectrometry can effectively be applicable to simultaneous quantification of multiple peptides.selected reaction monitoring (srm) mass spectrometry (ms) is becoming a popular approach for targeted quantitative proteomics. triple-quadrupole mass spectrometers have been historically considered as the instrument of choice for this type of quantitative analysis. recently, however, it has been reported that the srm ms with a linear ion-trap (lit) mass spectrometer is rather more appropriate for quantitative analysis of large peptides than the triple-quadrupole ones. in this study, we demonstra ...201121212531
candida albicans sfl2, a temperature-induced transcriptional regulator, is required for virulence in a murine gastrointestinal infection model.many transcriptional regulators play roles in morphogenesis of the human pathogen candida albicans. recently, sfl2, a sequence homolog of c. albicans sfl1, has been shown to be required for hyphal development. in this report, we show that, like sfl1, sfl2 could complement the phenotypes of the saccharomyces cerevisiae sfl1 mutant, and green fluorescent protein-tagged sfl2 localized in the nuclei of both yeast and hyphal cells in c. albicans, reflecting its role as a transcriptional regulator. in ...201121205158
crystal structure of the middle domain of human poly(a)-binding protein-interacting protein 1.in eukaryotes, the poly(a)-binding protein (pabp) is one of the important factors for initiation of messenger rna translation. pabp activity is regulated by the pabp-interacting proteins (paips), which include paip1, paip2a, and paip2b. human paip1 has three different isoforms. here, we report the crystal structure of the middle domain of paip1 isoform 2 (paip1m) as determined by single-wavelength anomalous dispersion phasing. the structure reveals a crescent-shaped domain consisting of 10 α-hel ...201121539810
a comprehensive platform for highly multiplexed mammalian functional genetic screens.abstract: background: genome-wide screening in human and mouse cells using rna interference and open reading frame over-expression libraries is rapidly becoming a viable experimental approach for many research labs. there are a variety of gene expression modulation libraries commercially available, however, detailed and validated protocols as well as the reagents necessary for deconvolving genome-scale gene screens using these libraries are lacking. as a solution, we designed a comprehensive pla ...201121548937
a missense mutation in prpf6 causes impairment of pre-mrna splicing and autosomal-dominant retinitis pigmentosa.retinitis pigmentosa (rp) is an inherited form of retinal degeneration that leads to progressive visual-field constriction and blindness. although the disease manifests only in the retina, mutations in ubiquitously expressed genes associated with the tri-snrnp complex of the spliceosome have been identified in patients with dominantly inherited rp. we screened for mutations in prpf6 (nm_012469.3), a gene on chromosome 20q13.33 encoding an essential protein for tri-snrnp assembly and stability, i ...201121549338
a hybrid model to study pathological mutations of the human adp/atp carriers.the adenine nucleotide carrier (ancp) plays an essential role in the metabolism of cellular energy by catalyzing the transport of adp and atp across the inner mitochondrial membrane. previous reports have indicated that mutations in the hanc1 gene, encoding the muscle isoform of human ancp (hanc1p), are directly involved in several diseases, including autosomal dominant progressive external ophthalmoplegia and cardiomyopathies. in this work, we studied three pathogenic hanc1 mutations at the bio ...201121549803
a combinatorial genetic library approach to target heterologous glycosylation enzymes to the endoplasmic reticulum or the golgi apparatus of pichia pastoris.to humanize the glycosylation pathway in the yeast pichia pastoris, we developed several combinatorial genetic libraries and used them to properly localize active eukaryotic mannosidases and sugar transferases. here we report the details of the fusion of up to 66 n-terminal targeting sequences of fungal type ii membrane proteins to 33 catalytic domains of heterologous glycosylation enzymes. we show that while it is difficult to predict which leader/catalytic domain will result in the desired act ...201121360735
many ways to build an actin filament.cells rely on extensive networks of protein fibres to help maintain their proper form and function. for species ranging from bacteria to humans, this 'cytoskeleton' is integrally involved in diverse processes including movement, dna segregation, cell division and transport of molecular cargoes. the most abundant cytoskeletal filament-forming protein, f-actin, is remarkably well conserved across eukaryotic species. from yeast to human - an evolutionary distance of over one billion years - only ab ...201121362063
measuring the evolutionary rate of protein-protein interaction.despite our extensive knowledge about the rate of protein sequence evolution for thousands of genes in hundreds of species, the corresponding rate of protein function evolution is virtually unknown, especially at the genomic scale. this lack of knowledge is primarily because of the huge diversity in protein function and the consequent difficulty in gauging and comparing rates of protein function evolution. nevertheless, most proteins function through interacting with other proteins, and protein- ...201121555556
ase1p phosphorylation by cyclin-dependent kinase promotes correct spindle assembly in s. cerevisiae.spindle morphogenesis and dynamics follow an orderly sequence of events coupled to the oscillatory activation of cyclin-dependent kinase (cdk). using s. cerevisiae we have addressed the requirement of cdk for phosphorylation of the spindle midzone component ase1p and its significance to spindle assembly. ase1p is related to human prc1, a protein negatively regulated by cdk until late mitosis when it is required for central spindle organization and cytokinesis. by contrast, we show here that ase1 ...201121558801
yeast as a model system to study tau biology.hyperphosphorylated and aggregated human protein tau constitutes a hallmark of a multitude of neurodegenerative diseases called tauopathies, exemplified by alzheimer's disease. in spite of an enormous amount of research performed on tau biology, several crucial questions concerning the mechanisms of tau toxicity remain unanswered. in this paper we will highlight some of the processes involved in tau biology and pathology, focusing on tau phosphorylation and the interplay with oxidative stress. i ...201121559193
identification of virulence determinants of the human pathogenic fungi aspergillus fumigatus and candida albicans by proteomics.both fungi candida albicans and aspergillus fumigatus can cause a number of life-threatening systemic infections in humans. the commensal yeast c. albicans is one of the main causes of nosocomial fungal infectious diseases, whereas the filamentous fungus a. fumigatus has become one of the most prevalent airborne fungal pathogens. early diagnosis of these fungal infections is challenging, only a limited number of antifungals for treatment are available, and the molecular details of pathogenicity ...201121565549
interaction with polyglutamine expanded huntingtin alters cellular distribution and rna processing of huntingtin yeast two-hybrid protein a (hypa).huntington's disease (hd) is an autosomal inherited disorder that causes the deterioration of brain cells. the polyglutamine (polyq) expansion of huntingtin (htt) is implicated in the pathogenesis of hd via interaction with an rna splicing factor, htt yeast two-hybrid protein a/formin binding protein 11 (hypa/fbp11). besides the pathogenic polyq expansion, htt also contains a proline-rich region (prr) located exactly in the c-terminus to the polyq tract. however, how the polyq expansion influenc ...201121566141
hsav1 interacts with hax1 and attenuates its anti-apoptotic effects in mcf-7 breast cancer cells.it has been reported that salvador (sav) is a core component of the salvador-warts-hippo (swh) pathway that restricts cell number, by functioning as a dual regulator of cell proliferation and apoptosis in drosophila. however, the function of its human ortholog hsav1 (also called hww45) in mammalian cells is poorly understood. in this study, we identified hematopoietic cell-specific protein 1 (hs1)-associated protein x-1 (hax1), a 35-kda protein localized to cell mitochondria, as a novel binding ...201121567072
maturation of human dendritic cells with saccharomyces cerevisiae (yeast) reduces the number and function of regulatory t cells and enhances the ratio of antigen-specific effectors to regulatory t cells.we compared the effects of yeast-treated human dendritic cells (dcs) with cd40l-matured human dcs for the induction of effector cells and the number and functionality of cd4(+)cd25(+)cd127(-)foxp3(+) regulatory t cells (tregs). dcs were treated with yeast or cd40l and cocultured with isolated autologous cd4(+) t cells. cd4(+)cd25(+)cd127(-) t cells isolated from the coculture of cd4(+) t cells plus yeast-treated dcs (yeast coculture) had a lower expression of foxp3 and decreased suppressive func ...201121569810
a universal code for rna recognition by puf proteins.the design of proteins that can bind any rna sequence of interest has many potential biological and medical applications. here we have expanded the recognition of pumilio and fbf homology protein (puf) repeats beyond adenine, guanine and uracil and evolved them to specifically bind cytosine. these repeat sequences can be used to create puf domains capable of selectively binding rna targets of diverse sequence and structure.201121572425
prin, a predicted rice interactome network.abstract: background: protein-protein interactions play a fundamental role in elucidating the molecular mechanisms of biomolecular function, signal transductions and metabolic pathways of living organisms. although high-throughput technologies such as yeast two-hybrid system and tandem mass spectrometry are widely used in model organisms, the progress of protein-protein interactions detection in plants is rather slow. with this motivation, our work presents a computational approach to predict pr ...201121575196
sirt3 and cancer: tumor promoter or suppressor?sirtuins (sirt1-7), the mammalian homologues of the sir2 gene in yeast, have emerging roles in age-related diseases, such as cardiac hypertrophy, diabetes, obesity, and cancer. however, the role of several sirtuin family members, including sirt1 and sirt3, in cancer has been controversial. the aim of this review is to explore and discuss the seemingly dichotomous role of sirt3 in cancer biology with particular emphasis on its potential role as a tumor promoter and tumor suppressor. this review w ...201121586315
the fungal pathogen candida albicans autoinduces hyphal morphogenesis by raising extracellular ph.abstract ph homeostasis is critical for all organisms; in the fungal pathogen candida albicans, ph adaptation is critical for virulence in distinct host niches. we demonstrate that beyond adaptation, c. albicans actively neutralizes the environment from either acidic or alkaline phs. under acidic conditions, this species can raise the ph from 4 to >7 in less than 12 h, resulting in autoinduction of the yeast-hyphal transition, a critical virulence trait. extracellular alkalinization has been rep ...201121586647
downstream of human ndr kinases: impacting on c-myc and p21 protein stability to control cell cycle progression.the mammalian genome encodes four members of the ndr/lats kinase family: ndr1 (stk38), ndr2 (stk38l), lats1 and lats2, which are highly conserved from yeast to man. members of the ndr/lats kinase family have been implicated in a variety of biological processes ranging from cell division and morphology to apoptosis and tumor suppression. in mammals lats1/2 function as central parts of the hippo tumor suppressor pathway by restricting the activity of the yap/taz proto-oncogenes. recent evidence su ...201121593588
presynaptic filament dynamics in homologous recombination and dna repair.homologous recombination (hr) is an essential genome stability mechanism used for high-fidelity repair of dna double-strand breaks and for the recovery of stalled or collapsed dna replication forks. the crucial homology search and dna strand exchange steps of hr are catalyzed by presynaptic filaments-helical filaments of a recombinase enzyme bound to single-stranded dna (ssdna). presynaptic filaments are fundamentally dynamic structures, the assembly, catalytic turnover, and disassembly of which ...201121599536
pinta: a web server for network-based gene prioritization from expression data.pinta (available at http://www.esat.kuleuven.be/pinta/; this web site is free and open to all users and there is no login requirement) is a web resource for the prioritization of candidate genes based on the differential expression of their neighborhood in a genome-wide protein-protein interaction network. our strategy is meant for biological and medical researchers aiming at identifying novel disease genes using disease specific expression data. pinta supports both candidate gene prioritization ...201121602267
the involvement of smile/tmtc3 in endoplasmic reticulum stress response.thestate of operational tolerance has been detected sporadically in some renal transplanted patients that stopped immunosuppressive drugs, demonstrating that allograft tolerance might exist in humans. several years ago, a study by brouard et al. identified a molecular signature of several genes that were significantly differentially expressed in the blood of such patients compared with patients with other clinical situations. the aim of the present study is to analyze the role of one of these mo ...201121603654
gisao.db: a database for ageing research.abstract: background: age-related gene expression patterns of homo sapiens as well as of model organisms such as mus musculus, saccharomyces cerevisiae, caenorhabditis elegans and drosophila melanogaster are a basis for understanding the genetic mechanisms of ageing. for an effective analysis and interpretation of expression profiles it is necessary to store and manage huge amounts of data in an organized way, so that these data can be accessed and processed easily. description gisao.db (genes i ...201121609420
identification of mek2-mapk kinase as a novel partner of the scaffolding protein human homolog of disc-large (hdlg).human disc-large homolog (hdlg), also known as synapse-associated protein 97 (sap97), is a scaffold protein, member of the membrane-associated guanylate kinase (maguk) family, implicated in neuronal synapses and epithelial-epithelial cell junctions whose expression and function remains poorly characterized in most tissues, particularly in the vasculature. our data show that, in human vascular tissues, hdlg is highly expressed in smooth muscle cells (vsmcs). using the yeast two-hybrid system to s ...201121615688
interaction of the receptor fgfrl1 with the negative regulator spred1.fgfrl1 is a member of the fibroblast growth factor receptor family. it plays an essential role during branching morphogenesis of the metanephric kidneys, as mice with a targeted deletion of the fgfrl1 gene show severe kidney dysplasia. here we used the yeast two-hybrid system to demonstrate that fgfrl1 binds with its c-terminal, histidine-rich domain to spred1 and to other proteins of the sprouty/spred family. members of this family are known to act as negative regulators of the ras/raf/erk sign ...201121616146
structure-function studies of an engineered scaffold protein derived from stefin a. ii: development and applications of the sqt variant.constrained binding peptides (peptide aptamers) may serve as tools to explore protein conformations and disrupt protein-protein interactions. the quality of the protein scaffold, by which the binding peptide is constrained and presented, is of crucial importance. sqt (stefin a quadruple mutant-tracy) is our most recent development in the stefin a-derived scaffold series. stefin a naturally uses three surfaces to interact with its targets. sqt tolerates peptide insertions at all three positions. ...201121616931
the role of hsl7 in morphology and pathogenicity and its interaction with other signaling components in the plant pathogen, ustilago maydis.the phytopathogenic fungus ustilago maydis undergoes a dimorphic transition in response to mating pheromone, host, and environmental cues. on solid media deficient in ammonium (slad), u. maydis produces a filamentous colony morphology, while in liquid slad the cells do not form filaments. the p21-activated protein kinases (paks) play a substantial role in regulating the dimorphic transition in fungi. the pak-like ste20 homologue, smu1, is required for a normal response to pheromone via up-regula ...201121622903
structure of the c-terminal domain of saccharomyces cerevisiae nup133, a component of the nuclear pore complex. 201121365675
connectedness of ppi network neighborhoods identifies regulatory hub proteins.with the growing availability of high-throughput protein-protein interaction (ppi) data, it has become possible to consider how a protein's local or global network characteristics predict its function.201121367871
caenorhabditis elegans aristaless/arx gene alr-1 restricts variable gene expression.variable expressivity of mutant phenotypes in genetically identical individuals is a phenomenon widely reported but poorly understood. for example, mutations in the gene encoding the transcription factor alr-1 in caenorhabditis elegans result in variable touch receptor neuron (trn) function. using single-molecule in situ hybridization, we demonstrate that this phenotypic variability reflects enhanced variability in the expression of the selector gene mec-3, which is needed, together with unc-86, ...201121368126
redox regulation of the tumor suppressor pten by glutaredoxin 5 and ycp4.human pten (phosphatase and tensin homolog deleted on chromosome 10; a phosphatidylinositol 3-phosphatase) expressed in saccharomyces cerevisiae was oxidized in a time- and h(2)o(2)-concentration-dependent manner. oxidized hpten was reduced by cellular reductants as in human cells. the reduction rate of oxidized hpten was monitored in s. cerevisiae mutants in which the genes involved in redox homeostasis had been disrupted. reduction of hpten was delayed in each of s. cerevisiae grx5? and ycp4? ...201121371429
endosomal targeting of the phosphoinositide 3-phosphatase mtmr2 is regulated by an n-terminal phosphorylation site.mtmr2 is a member of the myotubularin family of inositol lipid phosphatases, a large protein-tyrosine phosphatase subgroup that is conserved from yeast to humans. furthermore, the peripheral neuromuscular disease charcot-marie tooth disease type 4b has been attributed to mutations in the mtmr2 gene. because the molecular mechanisms regulating mtmr2 have been poorly defined, we investigated whether reversible phosphorylation might regulate mtmr2 function. we used mass spectrometry-based methods t ...201121372139
mpk1 mapk association with the paf1 complex blocks sen1-mediated premature transcription termination.the mpk1 mapk of the yeast cell wall integrity pathway uses a noncatalytic mechanism to activate transcription of stress-induced genes by recruitment of initiation factors to target promoters. we show here that mpk1 additionally serves a function in transcription elongation that is also independent of its catalytic activity. this function is mediated by an interaction between mpk1 and the paf1 subunit of the paf1c elongation complex. a mutation in paf1 that blocks this interaction causes a speci ...201121376235
proteome-derived peptide libraries allow detailed analysis of the substrate specificities of n(alpha)-acetyltransferases and point to hnaa10p as the post-translational actin n(alpha)-acetyltransferase.the impact of n(+¦)-terminal acetylation on protein stability and protein function in general recently acquired renewed and increasing attention. although the substrate specificity profile of the conserved enzymes responsible for n(+¦)-terminal acetylation in yeast has been well documented, the lack of higher eukaryotic models has hampered the specificity profile determination of n(+¦)-acetyltransferases (nats) of higher eukaryotes. the fact that several types of protein n termini are acetylated ...201121383206
aid induces double-strand breaks at immunoglobulin switch regions and c-myc causing chromosomal translocations in yeast tho mutants.transcription of the switch (s) regions of immunoglobulin genes in b cells generates stable r-loops that are targeted by activation induced cytidine deaminase (aid), triggering class switch recombination (csr), as well as translocations with c-myc responsible for burkitt's lymphomas. in saccharomyces cerevisiae, stable r-loops are formed co-transcriptionally in mutants of tho, a conserved nuclear complex involved in mrnp biogenesis. such r-loops trigger genome instability and facilitate deaminat ...201121383964
proteasome activator 200: the heat is on...proteasomes play a key regulatory role in all eukaryotic cells by removing proteins in a timely manner. there are two predominant forms: the 20s core particle (cp) can hydrolyze peptides and certain unstructured proteins, and the 26s holoenzyme is able to proteolyse most proteins conjugated to ubiquitin. the 26s complex consists of a cp barrel with a 19s regulatory particle (rp; a.k.a pa700) attached to its outer surface. several studies purified another proteasome activator with a mw of 200 kda ...201121389348
shprh and hltf act in a damage-specific manner to coordinate different forms of postreplication repair and prevent mutagenesis.postreplication repair (prr) pathways play important roles in restarting stalled replication forks and regulating mutagenesis. in yeast, rad5-mediated damage avoidance and rad18-mediated translesion synthesis (tls) are two forms of prr. two rad5-related proteins, shprh and hltf, have been identified in mammalian cells, but their specific roles in prr are unclear. here, we show that hltf and shprh suppress mutagenesis in a damage-specific manner, preventing mutations induced by uv and mms, respec ...201121396873
notch- and transducin-like enhancer of split (tle)-dependent histone deacetylation explain interleukin 12 (il-12) p70 inhibition by zymosan.the fungal analog zymosan induces il-23 and low amounts of il-12 p70. this study addresses the molecular mechanisms underlying this cytokine pattern in human monocyte-derived dendritic cells. the transcriptional regulation of il23a, one of the chains of il-23, depended on the activation of c-rel and histone h3 phosphorylation, as judged from the association of c-rel with the il23a promoter and the correlation between il-23 production and ser-10-histone h3 phosphorylation. consistent with its red ...201121402701
[os-9 and xtp3-b: lectins that regulate endoplasmic reticulum-associated degradation (erad)]. 201121404621
phosphate sensing.human phosphate homeostasis is regulated at the level of intestinal absorption of phosphate from the diet, release of phosphate through bone resorption, and renal phosphate excretion, and involves the actions of parathyroid hormone, 1,25-dihydroxy-vitamin d, and fibroblast growth factor 23 to maintain circulating phosphate levels within a narrow normal range, which is essential for numerous cellular functions, for the growth of tissues and for bone mineralization. prokaryotic and single cellular ...201121406298
fez2 has acquired additional protein interaction partners relative to fez1: functional and evolutionary implications.the fez (fasciculation and elongation protein zeta) family designation was purposed by bloom and horvitz by genetic analysis of c. elegans unc-76. similar human sequences were identified in the expressed sequence tag database as fez1 and fez2. the unc-76 function is necessary for normal axon fasciculation and is required for axon-axon interactions. indeed, the loss of unc-76 function results in defects in axonal transport. the human fez1 protein has been shown to rescue defects caused by unc-76 ...201121408165
novel applications for glycosylphosphatidylinositol-anchored proteins in pharmaceutical and industrial biotechnology.glycosylphosphatidylinositol (gpi)-anchored proteins have been regarded as typical cell surface proteins found in most eukaryotic cells from yeast to man. they are embedded in the outer plasma membrane leaflet via a carboxy-terminally linked complex glycolipid gpi structure. the amphiphilic nature of the gpi anchor, its compatibility with the function of the attached protein moiety and the capability of gpi-anchored proteins for spontaneous insertion into and transfer between artificial and cell ...201121413835
the type ii poly(a)-binding protein pabp-2 genetically interacts with the let-7 mirna and elicits heterochronic phenotypes in caenorhabditis elegans.the type ii poly(a)-binding protein pabp2/pabpn1 functions in general mrna metabolism by promoting poly(a) tail formation in mammals and flies. it also participates in poly(a) tail shortening of specific mrnas in flies, and snorna biogenesis in yeast. we have identified caenorhabditis elegans pabp-2 as a genetic interaction partner of the let-7 mirna, a widely conserved regulator of animal stem cell fates. depletion of pabp-2 by rnai suppresses loss of let-7 activity, and, in let-7 wild-type ani ...201121415013
i-ruby: a novel software for quantitative analysis of highly accurate shotgun-proteomics liquid chromatography/tandem mass spectrometry data obtained without stable-isotope labeling of proteins.we developed a novel software named i-ruby (identification-related quantification-based strategy algorithm for liquid chromatography/tandem mass spectrometry (lc/ms/ms) data) that enables us to perform fully automatic ion current-based spectral feature analysis of highly accurate data obtained by lc/ms/ms. at the 1st step, this software utilizes accurate peptide/protein identification information for peak detection and peak matching among measurements. then, at the 2nd step, it picks yet unident ...201121416533
beta-glucan from saccharomyces cerevisiae reduces plasma lipid peroxidation induced by haloperidol.since oxidative stress observed in schizophrenia may be caused partially by the treatment of patients with various antipsychotics, the aim of the study was to establish the effects of beta-d-glucan, polysaccharide derived from the yeast cell walls of species such as saccharomyces cerevisiae, and the antipsychotics (the first generation antipsychotic (fga) - haloperidol and the second generation antipsychotic (sga) - amisulpride) action on plasma lipid peroxidation in vitro. lipid peroxidation in ...201121421004
host cell targets of tegument protein vp22 of herpes simplex virus 1.in the present study, seven novel host cell factors associated with vp22 were identified from the human leukocyte cdna library using a yeast two-hybrid high-throughput screening system. to confirm some of the interactions, vp22 and its homologues and two candidate targets were tagged with enhanced cyan or yellow fluorescent protein. while ring finger protein 10 (rnf10), wd repeat-containing protein 42a (wdr42a) or vp22 alone showed distinct subcellular localization patterns, rnf10 and wdr42a wer ...201121424732
wwp2 is essential for palatogenesis mediated by the interaction between sox9 and mediator subunit 25.sox9 is a direct transcriptional activator of cartilage-specific extracellular matrix genes and has essential roles in chondrogenesis. mutations in or around the sox9 gene cause campomelic dysplasia or pierre robin sequence. however, sox9-dependent transcriptional control in chondrogenesis remains largely unknown. here we identify wwp2 as a direct target of sox9. wwp2 interacts physically with sox9 and is associated with sox9 transcriptional activity via its nuclear translocation. a yeast two-hy ...201121427722
a brief history of tor.the tor (target of rapamycin) serine/threonine kinases are fascinating in that they influence many different aspects of eukaryote physiology including processes often dysregulated in disease. beginning with the initial characterization of rapamycin as an antifungal agent, studies with yeast have contributed greatly to our understanding of the molecular pathways in which tors operate. recently, building on advances in quantitative ms, the rapamycin-dependent phosphoproteome in the budding yeast s ...201121428915
a longer and healthier life with tor down-regulation: genetics and drugs.genetic down-regulation of a major nutrient-sensing pathway, tor (target of rapamycin) signalling, can improve health and extend lifespan in evolutionarily distant organisms such as yeast and mammals. recently, it has been demonstrated that treatment with a pharmacological inhibitor of the tor pathway, rapamycin, can replicate those findings and improve aging in a variety of model organisms. the proposed underlying anti-aging mechanisms are down-regulated translation, increased autophagy, altere ...201121428920
non-diamond blackfan anemia disorders of ribosome function: shwachman diamond syndrome and 5q- syndrome.a number of human disorders, dubbed ribosomopathies, are linked to impaired ribosome biogenesis or function. these include but are not limited to diamond blackfan anemia (dba), shwachman diamond syndrome (sds), and the 5q- myelodysplastic syndrome (mds). this review focuses on the latter two non-dba disorders of ribosome function. both sds and 5q- syndrome lead to impaired hematopoiesis and a predisposition to leukemia. sds, due to bi-allelic mutations of the sbds gene, is a multi-system disorde ...201121435510
cooperative nuclear localization sequences lend a novel role to the n-terminal region of msh6.human mismatch repair proteins msh2-msh6 play an essential role in maintaining genetic stability and preventing disease. while protein functions have been extensively studied, the substantial amino-terminal region (ntr*) of msh6 that is unique to eukaryotic proteins, has mostly evaded functional characterization. we demonstrate that a cluster of three nuclear localization signals (nls) in the ntr direct nuclear import. individual nlss are capable of partially directing cytoplasmic protein into t ...201121437237
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