Description
PNAS is one of the world's most-cited multidisciplinary scientific serials. Since its establishment in 1915, it continues to publish cutting-edge research reports, commentaries, reviews, perspectives, colloquium papers, and actions of the Academy. Coverage in PNAS spans the biological, physical, and social sciences. PNAS is published biweekly in print, and weekly online in PNAS Early Edition.
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9.43
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Other titles
Proceedings of the National Academy of Sciences of the United States of America (Online), Proceedings of the National Academy of Sciences of the United States of America, PNAS online, PNAS
ISSN
1091-6490
OCLC
35912523
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Document, Periodical, Internet resource
Document type
Internet Resource, Computer File, Journal / Magazine / Newspaper
Publications in this journal
Authors: Billen B, Spurny R, Brams M, van Elk R, Valera-Kummer S, Yakel JL, Voets T, Bertrand D, Smit AB, Ulens C
Proceedings of the National Academy of Sciences.
Authors: Liang Yang, Naofumi Handa, Bian Liu, Mark S Dillingham, Dale B Wigley, Stephen C Kowalczykowski
Proceedings of the National Academy of Sciences of the United States of America.
The RecBCD enzyme is a complex heterotrimeric helicase/nuclease that initiates recombination at double-stranded DNA breaks. In Escherichia coli, its activities are regulated by the octamericThe RecBCD enzyme is a complex heterotrimeric helicase/nuclease that initiates recombination at double-stranded DNA breaks. In Escherichia coli, its activities are regulated by the octameric recombination hotspot, χ (5'-GCTGGTGG), which is read as a single-stranded DNA sequence while the enzyme is unwinding DNA at over ∼1,000 bp/s. Previous studies implicated the RecC subunit as the "χ-scanning element" in this process. Site-directed mutagenesis and phenotypic analyses identified residues in RecC responsible for χ recognition [Handa N, et al., (2012) Proc Natl Acad Sci USA, 10.1073/pnas.1206076109]. The genetic analyses revealed two classes of mutants. Here we use ensemble and single-molecule criteria to biochemically establish that one class of mutants (type 1) has lost the capacity to recognize χ (lost-recognition), whereas the second class (type 2) has a lowered specificity for recognition (relaxed-specificity). The relaxed-specificity mutants still recognize canonical χ, but they have gained the capacity to precociously recognize single-nucleotide variants of χ. Based on the RecBCD structure, these mutant classes define an α-helix responsible for χ recognition that is allosterically coupled to a structural latch. When opened, we propose that the latch permits access to an alternative exit channel for the single-stranded DNA downstream of χ, thereby avoiding degradation by the nuclease domain. These findings provide a unique perspective into the mechanism by which recognition of a single-stranded DNA sequence switches the translocating RecBCD from a destructive nuclease to a constructive component of recombinational DNA repair.
Authors: Massimiliano di Pietro, Pierre Lao-Sirieix, Shelagh Boyle, Andy Cassidy, Dani Castillo, Amel Saadi, Ragnhild Eskeland, Rebecca C Fitzgerald
Proceedings of the National Academy of Sciences of the United States of America.
Barrett esophagus (BE) is a human metaplastic condition that is the only known precursor to esophageal adenocarcinoma. BE is characterized by a posterior intestinal-like phenotype in an anteriorBarrett esophagus (BE) is a human metaplastic condition that is the only known precursor to esophageal adenocarcinoma. BE is characterized by a posterior intestinal-like phenotype in an anterior organ and therefore it is reminiscent of homeotic transformations, which can occur in transgenic animal models during embryonic development as a consequence of mutations in HOX genes. In humans, acquired deregulation of HOX genes during adulthood has been linked to carcinogenesis; however, little is known about their role in the pathogenesis of premalignant conditions. We hypothesized that HOX genes may be implicated in the development of BE. We demonstrated that three midcluster HOXB genes (HOXB5, HOXB6, and HOXB7) are overexpressed in BE, compared with the anatomically adjacent normal esophagus and gastric cardia. The midcluster HOXB gene signature in BE is identical to that seen in normal colonic epithelium. Ectopic expression of these three genes in normal squamous esophageal cells in vitro induces markers of intestinal differentiation, such as KRT20, MUC2, and VILLIN. In BE-associated adenocarcinoma, the activation midcluster HOXB gene is associated with loss of H3K27me3 and gain of AcH3, compared with normal esophagus. These changes in histone posttranslational modifications correlate with specific chromatin decompaction at the HOXB locus. We suggest that epigenetically regulated alterations of HOX gene expression can trigger changes in the transcriptional program of adult esophageal cells, with implications for the early stages of carcinogenesis.
Authors: Naofumi Handa, Liang Yang, Mark S Dillingham, Ichizo Kobayashi, Dale B Wigley, Stephen C Kowalczykowski
Proceedings of the National Academy of Sciences of the United States of America.
The RecBCD enzyme is important for both restriction of foreign DNA and recombinational DNA repair. Switching enzyme function from the destructive antiviral state to the productive recombinationalThe RecBCD enzyme is important for both restriction of foreign DNA and recombinational DNA repair. Switching enzyme function from the destructive antiviral state to the productive recombinational state is regulated by the recombination hotspot, χ (5'-GCTGGTGG-3'). Recognition of χ is unique in that it is recognized as a specific sequence within single-stranded DNA (ssDNA) during DNA translocation and unwinding by RecBCD. The molecular determinants of χ recognition and the subsequent alteration in function are unknown. Consequently, we mutated residues within the RecC subunit that comprise a channel where ssDNA is thought to be scanned for a χ sequence. These mutants were characterized in vivo with regard to χ recognition, UV-sensitivity, phage degradation, and recombination proficiency. Of 38 residues mutated, 11 were previously undescribed mutations that altered χ recognition. The mutants fell into two classes: five that failed to respond to χ, and six that suggested a relaxed specificity for χ recognition. The location of the first set of mutations defines a recognition structure responsible for sequence-specific binding of ssDNA. The second set defines a highly conserved structure, linked to the recognition structure, which we hypothesize regulates conversion of RecBCD from a molecular machine that destroys DNA to one that repairs it. These findings offer insight into the evolution of enzymes with alternate χ recognition specificities.
Authors: Carmen Domene
Proceedings of the National Academy of Sciences of the United States of America.
Authors: Israel Ausin, Maxim V C Greenberg, Dhirendra K Simanshu, Christopher J Hale, Ajay A Vashisht, Stacey A Simon, Tzuu-Fen Lee, Suhua Feng, Sophia D Española, Blake C Meyers, James A Wohlschlegel, Dinshaw J Patel, Steven E Jacobsen
Proceedings of the National Academy of Sciences of the United States of America.
At least three pathways control maintenance of DNA cytosine methylation in Arabidopsis thaliana. However, the RNA-directed DNA methylation (RdDM) pathway is solely responsible for establishment ofAt least three pathways control maintenance of DNA cytosine methylation in Arabidopsis thaliana. However, the RNA-directed DNA methylation (RdDM) pathway is solely responsible for establishment of this silencing mark. We previously described INVOLVED IN DE NOVO 2 (IDN2) as being an RNA-binding RdDM component that is required for DNA methylation establishment. In this study, we describe the discovery of two partially redundant proteins that are paralogous to IDN2 and that form a stable complex with IDN2 in vivo. Null mutations in both genes, termed IDN2-LIKE 1 and IDN2-LIKE 2 (IDNL1 and IDNL2), result in a phenotype that mirrors, but does not further enhance, the idn2 mutant phenotype. Genetic analysis suggests that this complex acts in a step in the downstream portion of the RdDM pathway. We also have performed structural analysis showing that the IDN2 XS domain adopts an RNA recognition motif (RRM) fold. Finally, genome-wide DNA methylation and expression analysis confirms the placement of the IDN proteins in an RdDM pathway that affects DNA methylation and transcriptional control at many sites in the genome. Results from this study identify and describe two unique components of the RdDM machinery, adding to our understanding of DNA methylation control in the Arabidopsis genome.
Authors: Brian R Daniels, Richa Rikhy, Malte Renz, Terrence M Dobrowsky, Jennifer Lippincott-Schwartz
Proceedings of the National Academy of Sciences of the United States of America.
Despite the fundamental importance of diffusion for embryonic morphogen gradient formation in the early Drosophila melanogaster embryo, there remains controversy regarding both the extent and theDespite the fundamental importance of diffusion for embryonic morphogen gradient formation in the early Drosophila melanogaster embryo, there remains controversy regarding both the extent and the rate of diffusion of well-characterized morphogens. Furthermore, the recent observation of diffusional "compartmentalization" has suggested that diffusion may in fact be nonideal and mediated by an as-yet-unidentified mechanism. Here, we characterize the effects of the geometry of the early syncytial Drosophila embryo on the effective diffusivity of cytoplasmic proteins. Our results demonstrate that the presence of transient mitotic membrane furrows results in a multiscale diffusion effect that has a significant impact on effective diffusion rates across the embryo. Using a combination of live-cell experiments and computational modeling, we characterize these effects and relate effective bulk diffusion rates to instantaneous diffusion coefficients throughout the syncytial blastoderm nuclear cycle phase of the early embryo. This multiscale effect may be related to the effect of interphase nuclei on effective diffusion, and thus we propose that an as-yet-unidentified role of syncytial membrane furrows is to temporally regulate bulk embryonic diffusion rates to balance the multiscale effect of interphase nuclei, which ultimately stabilizes the shapes of various morphogen gradients.
Authors: Julie Collet, David S Richardson, Kirsty Worley, Tommaso Pizzari
Proceedings of the National Academy of Sciences of the United States of America.
In principle, widespread polyandry (female promiscuity) creates potential for sexual selection in males both before and after copulation. However, the way polyandry affects pre- and postcopulatoryIn principle, widespread polyandry (female promiscuity) creates potential for sexual selection in males both before and after copulation. However, the way polyandry affects pre- and postcopulatory episodes of sexual selection remains little understood. Resolving this fundamental question has been difficult because it requires extensive information on mating behavior as well as paternity for the whole male population. Here we show that in replicate seminatural groups of red junglefowl, Gallus gallus, polyandry eroded variance in male mating success, which simultaneously weakened the overall intensity of sexual selection but increased the relative strength of postcopulatory episodes. We further illustrate the differential effect of polyandry on pre- and postcopulatory sexual selection by considering the case of male social status, a key determinant of male reproductive success in this species. In low-polyandry groups, however, status was strongly sexually selected before copulation because dominants mated with more females. In high-polyandry groups, sexual selection for status was weakened and largely restricted after copulation because dominants defended paternity by mating repeatedly with the same female. These results reveal polyandry as a potent and dynamic modulator of sexual selection episodes.
Authors: Marc Aurel Busche, Xiaowei Chen, Horst A Henning, Julia Reichwald, Matthias Staufenbiel, Bert Sakmann, Arthur Konnerth
Proceedings of the National Academy of Sciences of the United States of America.
Alzheimer's disease (AD) is characterized by a progressive dysfunction of central neurons. Recent experimental evidence indicates that in the cortex, in addition to the silencing of a fraction ofAlzheimer's disease (AD) is characterized by a progressive dysfunction of central neurons. Recent experimental evidence indicates that in the cortex, in addition to the silencing of a fraction of neurons, other neurons are hyperactive in amyloid-β (Aβ) plaque-enriched regions. However, it has remained unknown what comes first, neuronal silencing or hyperactivity, and what mechanisms might underlie the primary neuronal dysfunction. Here we examine the activity patterns of hippocampal CA1 neurons in a mouse model of AD in vivo using two-photon Ca(2+) imaging. We found that neuronal activity in the plaque-bearing CA1 region of older mice is profoundly altered. There was a marked increase in the fractions of both silent and hyperactive neurons, as previously also found in the cortex. Remarkably, in the hippocampus of young mice, we observed a selective increase in hyperactive neurons already before the formation of plaques, suggesting that soluble species of Aβ may underlie this impairment. Indeed, we found that acute treatment with the γ-secretase inhibitor LY-411575 reduces soluble Aβ levels and rescues the neuronal dysfunction. Furthermore, we demonstrate that direct application of soluble Aβ can induce neuronal hyperactivity in wild-type mice. Thus, our study identifies hippocampal hyperactivity as a very early functional impairment in AD transgenic mice and provides direct evidence that soluble Aβ is crucial for hippocampal hyperactivity.
Authors: Yanping Wang, Steven J Marling, Jinge G Zhu, Kyle S Severson, Hector F Deluca
Proceedings of the National Academy of Sciences of the United States of America.
The development of experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis, has been studied in mice that were (i) vitamin D-deficient, (ii) minus the vitamin D receptor, (iii)The development of experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis, has been studied in mice that were (i) vitamin D-deficient, (ii) minus the vitamin D receptor, (iii) minus a vitamin D 25-hydroxylase, and (iv) minus the vitamin D 25-hydroxyvitamin D-1α-hydroxylase. EAE development was markedly suppressed in mice lacking the vitamin D receptor and partially suppressed in vitamin D-insufficient mice. However, the absence of either of the two key hydroxylases (i.e., 25-hydroxylase and 1α-hydroxylase) neither inhibits nor enhances the development of EAE. These results indicate that vitamin D and the vitamin D receptor are required for the development of EAE. The results also suggest that 1,25-dihydroxyvitamin D(3) may not play a role in this autoimmune response.
Authors: M Sinan Özeren
Proceedings of the National Academy of Sciences of the United States of America.
Present-day crust-mantle coupling in the Eastern Mediterranean and eastern Turkey is studied using the Global Positioning System (GPS) and seismic anisotropy data. The general trend of the shear wavePresent-day crust-mantle coupling in the Eastern Mediterranean and eastern Turkey is studied using the Global Positioning System (GPS) and seismic anisotropy data. The general trend of the shear wave fast-splitting directions in NE Turkey and Lesser Caucaus align well with the geodetic velocities in an absolute plate motion frame of reference pointing to an effective coupling in this part of the region of weak surface deformation. Farther south, underneath the Bitlis Suture, however, there are significant Pn delays with E-W anisotropy axes indicating significant lateral escape. Meanwhile, the GPS reveals very little surface deformation. This mismatch possibly suggests a decoupling along the suture. In the Aegean, the shear wave anisotropy and the Pn anisotropy directions agree with the extensional component of the right-lateral shear strains except under the Crete Basin and other parts of the southern Aegean Sea. This extensional direction matches perfectly also with the southward pulling force vectors across the Hellenic trench; however, the maximum right-lateral shear directions obtained from the GPS data in the Aegean do not match either of these anisotropies. Seismic anisotropy from Rayleigh waves sampled at 15 s, corresponding to the lower crust, match the maximum right-lateral maximum shear directions from the GPS indicating decoupling between the crust and the mantle. This decoupling most likely results from the lateral variations of the gravitational potential energies and the slab-pull forces.
Authors: Aaron Kheifets, C R Gallistel
Proceedings of the National Academy of Sciences of the United States of America.
Animals successfully navigate the world despite having only incomplete information about behaviorally important contingencies. It is an open question to what degree this behavior is driven byAnimals successfully navigate the world despite having only incomplete information about behaviorally important contingencies. It is an open question to what degree this behavior is driven by estimates of stochastic parameters (brain-constructed models of the experienced world) and to what degree it is directed by reinforcement-driven processes that optimize behavior in the limit without estimating stochastic parameters (model-free adaptation processes, such as associative learning). We find that mice adjust their behavior in response to a change in probability more quickly and abruptly than can be explained by differential reinforcement. Our results imply that mice represent probabilities and perform calculations over them to optimize their behavior, even when the optimization produces negligible material gain.
Authors: Hui Zhao, Dandan Han, Igor B Dawid, Tomas Pieler, Yonglong Chen
Proceedings of the National Academy of Sciences of the United States of America.
Liver and ventral pancreas develop from neighboring territories within the endoderm of gastrulae. ventral pancreatic precursor 1 (vpp1) is a marker gene that is differentially expressed in a cellLiver and ventral pancreas develop from neighboring territories within the endoderm of gastrulae. ventral pancreatic precursor 1 (vpp1) is a marker gene that is differentially expressed in a cell population within the dorsal endoderm in a pattern partially overlapping with that of hematopoietically expressed homeobox (hhex) during gastrulation. In tail bud embryos, vpp1 expression specifically demarcates two ventral pancreatic buds, whereas hhex expression is mainly restricted to the liver diverticulum. Ectopic expression of a critical dose of hhex led to a greatly enlarged vpp1-positive domain and, subsequently, to the formation of giant ventral pancreata, putatively by conversion of intestinal to ventral pancreatic precursor cells. Conversely, antisense morpholino oligonucleotide-mediated knockdown of hhex resulted in a down-regulation of vpp1 expression and a specific loss of the ventral pancreas. Furthermore, titration of hhex with a dexamethasone-inducible hhex-VP16GR fusion construct suggested that endogenous hhex activity during gastrulation is essential for the formation of ventral pancreatic progenitor cells. These observations suggest that, beyond its role in liver development, hhex controls specification of a vpp1-positive endodermal cell population during gastrulation that is required for the formation of the ventral pancreas.
Authors: Tim Willinger, Richard A Flavell
Proceedings of the National Academy of Sciences of the United States of America.
The homeostasis of naive T cells is essential for protective immunity against infection, but the cell-intrinsic molecular mechanisms that control naïve T-cell homeostasis are poorly understood.The homeostasis of naive T cells is essential for protective immunity against infection, but the cell-intrinsic molecular mechanisms that control naïve T-cell homeostasis are poorly understood. Genetic ablation in lower organisms has revealed a critical role for Vps34, an evolutionary conserved class III phosphoinositide-3 kinase (PI3K), in regulating endocytosis and autophagy; however, the physiological function of Vps34 in the immune system, especially in T cells, is unclear. Here we report that Vps34 is required for the maintenance of naïve T cells, acting in a cell-intrinsic manner. T-cell-specific deletion of the gene encoding Vps34 resulted in reduced stability of Vps15 and Beclin-1, components of the class III PI3K complex, and impaired autophagy in T cells. Vps34 was dispensable for T-cell development but important for the survival of naïve T cells. Vps34-deficient T cells showed increased mitochondrial mass and accumulation of reactive oxygen species, consistent with deficient removal of damaged mitochondria. Thus, Vps34-dependent canonical autophagy plays a critical role in maintaining T-cell homeostasis by promoting T-cell survival through quality control of mitochondria.
Authors: Aaron J Schetter, Curtis C Harris
Proceedings of the National Academy of Sciences of the United States of America.
Authors: Andrea Rossi, Julien Ratelade, Marios C Papadopoulos, Jeffrey L Bennett, A S Verkman
Proceedings of the National Academy of Sciences of the United States of America.
Authors: Jessica V Hankins, James A Madsen, David K Giles, Jennifer S Brodbelt, M Stephen Trent
Proceedings of the National Academy of Sciences of the United States of America.
Historically, the O1 El Tor and classical biotypes of Vibrio cholerae have been differentiated by their resistance to the antimicrobial peptide polymyxin B. However, the molecular mechanismsHistorically, the O1 El Tor and classical biotypes of Vibrio cholerae have been differentiated by their resistance to the antimicrobial peptide polymyxin B. However, the molecular mechanisms associated with this phenotypic distinction have remained a mystery for 50 y. Both Gram-negative and Gram-positive bacteria modify their cell wall components with amine-containing substituents to reduce the net negative charge of the bacterial surface, thereby promoting cationic antimicrobial peptide resistance. In the present study, we demonstrate that V. cholerae modify the lipid A anchor of LPS with glycine and diglycine residues. This previously uncharacterized lipid A modification confers polymyxin resistance in V. cholerae El Tor, requiring three V. cholerae proteins: Vc1577 (AlmG), Vc1578 (AlmF), and Vc1579 (AlmE). Interestingly, the protein machinery required for glycine addition is reminiscent of the Gram-positive system responsible for D-alanylation of teichoic acids. Such machinery was not thought to be used by Gram-negative organisms. V. cholerae O1 El Tor mutants lacking genes involved in transferring glycine to LPS showed a 100-fold increase in sensitivity to polymyxin B. This work reveals a unique lipid A modification and demonstrates a charge-based remodeling strategy shared between Gram-positive and Gram-negative organisms.
Authors: Chunlin Wang, Sujatha Krishnakumar, Julie Wilhelmy, Farbod Babrzadeh, Lilit Stepanyan, Laura F Su, Douglas Levinson, Marcelo A Fernandez-Viña, Ronald W Davis, Mark M Davis, Michael Mindrinos
Proceedings of the National Academy of Sciences of the United States of America.
Human leukocyte antigen (HLA) genes are the most polymorphic in the human genome. They play a pivotal role in the immune response and have been implicated in numerous human pathologies, especiallyHuman leukocyte antigen (HLA) genes are the most polymorphic in the human genome. They play a pivotal role in the immune response and have been implicated in numerous human pathologies, especially autoimmunity and infectious diseases. Despite their importance, however, they are rarely characterized comprehensively because of the prohibitive cost of standard technologies and the technical challenges of accurately discriminating between these highly related genes and their many allelles. Here we demonstrate a high-resolution, and cost-effective methodology to type HLA genes by sequencing, which combines the advantage of long-range amplification, the power of high-throughput sequencing platforms, and a unique genotyping algorithm. We calibrated our method for HLA-A, -B, -C, and -DRB1 genes with both reference cell lines and clinical samples and identified several previously undescribed alleles with mismatches, insertions, and deletions. We have further demonstrated the utility of this method in a clinical setting by typing five clinical samples in an Illumina MiSeq instrument with a 5-d turnaround. Overall, this technology has the capacity to deliver low-cost, high-throughput, and accurate HLA typing by multiplexing thousands of samples in a single sequencing run, which will enable comprehensive disease-association studies with large cohorts. Furthermore, this approach can also be extended to include other polymorphic genes.
Authors: Amparo Ruiz, Yang Liu, Xinjing Xu, Marian Carlson
Proceedings of the National Academy of Sciences of the United States of America.
The SNF1/AMP-activated protein kinases are αβγ-heterotrimers that sense and regulate energy status in eukaryotes. They are activated by phosphorylation of the catalytic Snf1/α subunit, and the Snf4/γThe SNF1/AMP-activated protein kinases are αβγ-heterotrimers that sense and regulate energy status in eukaryotes. They are activated by phosphorylation of the catalytic Snf1/α subunit, and the Snf4/γ regulatory subunit regulates phosphorylation through adenine nucleotide binding. In Saccharomyces cerevisiae, the Snf1 subunit is phosphorylated on the activation-loop Thr-210 in response to glucose limitation. To assess the requirement of the heterotrimer for regulated Thr-210 phosphorylation, we examined Snf1 and a truncated Snf1 kinase domain (residues 1-309) that has partial Snf1 function. Snf1(1-309) does not interact with the β and Snf4/γ regulatory subunits, and its activity was independent of them in vivo. Phosphorylation of both Snf1 and Snf1(1-309) increased in response to glucose limitation in wild-type cells and in cells lacking β- and Snf4/γ-subunits. These results indicate that glucose regulation of activation-loop phosphorylation can occur by mechanism(s) that function independently of the regulatory subunits. We further show that the Reg1-Glc7 protein phosphatase 1 and Sit4 type 2A-like phosphatase are largely responsible for dephosphorylation of Thr-210 of Snf1(1-309). Together, these findings suggest that these two phosphatases mediate heterotrimer-independent regulation of Thr-210 phosphorylation.
Authors: Sebastian Aeffner, Tobias Reusch, Britta Weinhausen, Tim Salditt
Proceedings of the National Academy of Sciences of the United States of America.
We have used X-ray diffraction on the rhombohedral phospholipid phase to reconstruct stalk structures in different pure lipids and lipid mixtures with unprecedented resolution, enabling aWe have used X-ray diffraction on the rhombohedral phospholipid phase to reconstruct stalk structures in different pure lipids and lipid mixtures with unprecedented resolution, enabling a quantitative analysis of geometry, as well as curvature and hydration energies. Electron density isosurfaces are used to study shape and curvature properties of the bent lipid monolayers. We observe that the stalk structure is highly universal in different lipid systems. The associated curvatures change in a subtle, but systematic fashion upon changes in lipid composition. In addition, we have studied the hydration interaction prior to the transition from the lamellar to the stalk phase. The results indicate that facilitating dehydration is the key to promote stalk formation, which becomes favorable at an approximately constant interbilayer separation of 9.0 ± 0.5 Å for the investigated lipid compositions.
Authors: Oddbjørn Straume, Takeshi Shimamura, Michael J G Lampa, Julian Carretero, Anne M Oyan, Di Jia, Christa L Borgman, Margaret Soucheray, Sean R Downing, Sarah M Short [......] Liang Chen, Karin Collett, Ingeborg Bachmann, Kwok-Kin Wong, Geoffrey I Shapiro, Karl Henning Kalland, Judah Folkman, Randolph S Watnick, Lars A Akslen, George N Naumov
Proceedings of the National Academy of Sciences of the United States of America.
The mechanisms underlying tumor dormancy have been elusive and not well characterized. We recently published an experimental model for the study of human tumor dormancy and the role of angiogenesis,The mechanisms underlying tumor dormancy have been elusive and not well characterized. We recently published an experimental model for the study of human tumor dormancy and the role of angiogenesis, and reported that the angiogenic switch was preceded by a local increase in VEGF-A and basic fibroblast growth factor. In this breast cancer xenograft model (MDA-MB-436 cells), analysis of differentially expressed genes revealed that heat shock protein 27 (HSP27) was significantly up-regulated in angiogenic cells compared with nonangiogenic cells. The effect of HSP27 down-regulation was further evaluated in cell lines, mouse models, and clinical datasets of human patients with breast cancer and melanoma. Stable down-regulation of HSP27 in angiogenic tumor cells was followed by long-term tumor dormancy in vivo. Strikingly, only 4 of 30 HSP27 knockdown xenograft tumors initiated rapid growth after day 70, in correlation with a regain of HSP27 protein expression. Significantly, no tumors escaped from dormancy without HSP27 expression. Down-regulation of HSP27 was associated with reduced endothelial cell proliferation and decreased secretion of VEGF-A, VEGF-C, and basic fibroblast growth factor. Conversely, overexpression of HSP27 in nonangiogenic cells resulted in expansive tumor growth in vivo. By clinical validation, strong HSP27 protein expression was associated with markers of aggressive tumors and decreased survival in patients with breast cancer and melanoma. An HSP27-associated gene expression signature was related to molecular subgroups and survival in breast cancer. Our findings suggest a role for HSP27 in the balance between tumor dormancy and tumor progression, mediated by tumor-vascular interactions. Targeting HSP27 might offer a useful strategy in cancer treatment.
Authors: Danielle K Rajani, Michael Walch, Denis Martinvalet, Marshall P Thomas, Judy Lieberman
Proceedings of the National Academy of Sciences of the United States of America.
During immune-mediated death, death-inducing granzyme (Gzm) proteases concentrate in the nucleus of cells targeted for immune elimination, suggesting that nuclear processes are important targets.During immune-mediated death, death-inducing granzyme (Gzm) proteases concentrate in the nucleus of cells targeted for immune elimination, suggesting that nuclear processes are important targets. Here we used differential 2D proteomics of GzmA-treated nuclei to identify potential GzmA substrates. Of 44 candidates, 33 were RNA-binding proteins important in posttranscriptional RNA processing, including 14 heterogeneous nuclear ribonucleoproteins (hnRNP). Multiple hnRNPs were degraded in cells undergoing GzmA-, GzmB-, or caspase-mediated death. GzmA and caspase activation impaired nuclear export of newly synthesized RNA and disrupted pre-mRNA splicing. Expressing GzmA-resistant hnRNP A1 inhibited GzmA-mediated cell death and rescued pre-mRNA splicing, suggesting that hnRNP A1 is an important GzmA substrate. Cellular stresses are known to inhibit initiation of cap-dependent translation. Disrupting pre-mRNA processing should block further new protein synthesis and promote death by interfering with pathways induced to protect cells from death.
Authors: Michael T Vagnini, Amanda L Smeigh, James D Blakemore, Samuel W Eaton, Nathan D Schley, Francis D'Souza, Robert H Crabtree, Gary W Brudvig, Dick T Co, Michael R Wasielewski
Proceedings of the National Academy of Sciences of the United States of America.
Photodriving the activity of water-oxidation catalysts is a critical step toward generating fuel from sunlight. The design of a system with optimal energetics and kinetics requires a mechanisticPhotodriving the activity of water-oxidation catalysts is a critical step toward generating fuel from sunlight. The design of a system with optimal energetics and kinetics requires a mechanistic understanding of the single-electron transfer events in catalyst activation. To this end, we report here the synthesis and photophysical characterization of two covalently bound chromophore-catalyst electron transfer dyads, in which the dyes are derivatives of the strong photooxidant perylene-3,4:9,10-bis(dicarboximide) (PDI) and the molecular catalyst is the Cp(∗)Ir(ppy)Cl metal complex, where ppy = 2-phenylpyridine. Photoexcitation of the PDI in each dyad results in reduction of the chromophore to PDI(•-) in less than 10 ps, a process that outcompetes any generation of (3∗)PDI by spin-orbit-induced intersystem crossing. Biexponential charge recombination largely to the PDI-Ir(III) ground state is suggestive of multiple populations of the PDI(•-)-Ir(IV) ion-pair, whose relative abundance varies with solvent polarity. Electrochemical studies of the dyads show strong irreversible oxidation current similar to that seen for model catalysts, indicating that the catalytic integrity of the metal complex is maintained upon attachment to the high molecular weight photosensitizer.
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