Abstract:
:The antiangiogenic agent fumagillin (Fg) and its analog TNP-470 bind to intracellular metalloprotease methionine aminopeptidase-2 (MetAP-2) and inhibit endothelial cell growth in a p53-dependent manner. To confirm the role of MetAP-2 in endothelial cell proliferation and to validate it as a physiological target for the Fg class of antiangiogenic agents, we have generated a conditional MetAP-2 knockout mouse. Ubiquitous deletion of the MetAP-2 gene (MAP2) resulted in an early gastrulation defect, which is bypassed in double MetAP-2/p53 knockout embryos. Targeted deletion of MAP2 specifically in the hemangioblast lineage resulted in abnormal vascular development, and these embryos die at the midsomite stage. In addition, knockdown of MetAP-2 using small interfering RNA or homologous recombination specifically suppresses the proliferation of cultured endothelial cells. Together, these results demonstrate an essential role for MetAP-2 in angiogenesis and indicate that MetAP-2 is responsible for the endothelial cell growth arrest induced by Fg and its derivatives.
journal_name
Proc Natl Acad Sci U S Aauthors
Yeh JJ,Ju R,Brdlik CM,Zhang W,Zhang Y,Matyskiela ME,Shotwell JD,Crews CMdoi
10.1073/pnas.0511313103subject
Has Abstractpub_date
2006-07-05 00:00:00pages
10379-10384issue
27eissn
0027-8424issn
1091-6490pii
0511313103journal_volume
103pub_type
杂志文章abstract::Expression cloning of cDNAs was first described a decade ago and was based on transient expression of cDNA libraries in COS cells. In contrast to transient transfection of plasmids, retroviral gene transfer delivers genes stably into a wide range of target cells. We utilize a simple packaging system for production of ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.92.20.9146
更新日期:1995-09-26 00:00:00
abstract::Oscillatory activity is widespread in dynamic neuronal networks. The main paradigm for the origin of periodicity consists of specialized pacemaking elements that synchronize and drive the rest of the network; however, other models exist. Here, we studied the spontaneous emergence of synchronized periodic bursting in a...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1515105113
更新日期:2016-03-22 00:00:00
abstract::The guanidinium group of arginine-166 has been postulated to act as an electrophilic species during phosphorylation of alkaline phosphatase. Its role could be either to stabilize the developing negative charge on the oxygen of the leaving group or the pentacoordinate transition state or to help bind the -PO2-3 group. ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.85.12.4276
更新日期:1988-06-01 00:00:00
abstract::The perinuclear localization of myosin-V was investigated in a variety of cultured mammalian cells and in primary cultures of rat hippocampus. In all cells investigated, myosin-V immunoreactivity was associated with the centrosome. In interphase cells, myosin-V was found in pericentriolar material, and in both mother ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.95.15.8636
更新日期:1998-07-21 00:00:00
abstract::ATP-sensitive potassium channels (K(ATP)) are involved in a diverse array of physiologic functions including protection of tissue against ischemic insult, regulation of vascular tone, and modulation of insulin secretion. To improve our understanding of the role of K(ATP) in these processes, we used a gene-targeting st...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.201390398
更新日期:2001-09-25 00:00:00
abstract::Nanophthalmos is a rare disorder of eye development characterized by extreme hyperopia (farsightedness), with refractive error in the range of +8.00 to +25.00 diopters. Because the cornea and lens are normal in size and shape, hyperopia occurs because insufficient growth along the visual axis places these lensing comp...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0501451102
更新日期:2005-07-05 00:00:00
abstract::One way to dissect the antibody response to an invading microorganism is to clone the antibody repertoire from immune donors and subsequently characterize the specific antibodies. Recently, methodological advances have allowed investigations of neutralizing antibodies against hepatitis C virus (HCV) in vitro. We have ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0705522104
更新日期:2007-10-09 00:00:00
abstract::Telomere syndromes have their most common manifestation in lung disease that is recognized as idiopathic pulmonary fibrosis and emphysema. In both conditions, there is loss of alveolar integrity, but the underlying mechanisms are not known. We tested the capacity of alveolar epithelial and stromal cells from mice with...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1504780112
更新日期:2015-04-21 00:00:00
abstract::Male (NZW x BXSB)F1 (W/BF1) mice develop systemic autoimmunity involving autoantibodies, thrombocytopenia, lupus nephritis, and coronary vascular disease (CVD) with myocardial infarction. To determine whether this murine lupus-associated CVD can be prevented by the reduction of dietary calories, male W/BF1 mice were s...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.91.10.4402
更新日期:1994-05-10 00:00:00
abstract::Biological diversity reflects an underlying molecular diversity. The molecules found in nature may be regarded as solutions to challenges that have been confronted and overcome during molecular evolution. As our understanding of these solutions deepens, the efficiency with which we can discover and/or design new treat...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章,评审
doi:10.1073/pnas.92.1.75
更新日期:1995-01-03 00:00:00
abstract::Ca(2+) influx triggers the fusion of synaptic vesicles at the presynaptic active zone (AZ). Here we demonstrate a role of Ras-related in brain 3 (Rab3)-interacting molecules 2α and β (RIM2α and RIM2β) in clustering voltage-gated CaV1.3 Ca(2+) channels at the AZs of sensory inner hair cells (IHCs). We show that IHCs of...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1417207112
更新日期:2015-06-16 00:00:00
abstract::Banded iron formations (BIFs) record a time of extensive Fe deposition in the Precambrian oceans, but the sources and pathways for metals in BIFs remain controversial. Here, we present Fe- and Nd-isotope data that indicate two sources of Fe for the large BIF units deposited 2.5 billion y ago. High-εNd and -δ(56)Fe sig...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1505515112
更新日期:2015-07-07 00:00:00
abstract::The kinetics and order of rearrangements in the gene complex encoding T-cell-receptor beta chains were studied by Southern blot hybridization in a collection of hybridomas derived from fetal thymocytes at various stages of ontogeny (day 14 to day 17). Our results show a steady increase in the frequency of rearranged b...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.82.9.2925
更新日期:1985-05-01 00:00:00
abstract::Whole human blood was examined by (31)P nuclear magnetic resonance spectroscopy. Individual phosphates (alpha,beta,gamma) of ATP were identifiable, and two microenvironments appeared to be present for this molecule. When sequential recordings of freshly collected blood were made, 2,3-diphosphoglycerate was observed to...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.71.6.2487
更新日期:1974-06-01 00:00:00
abstract::The role of spliced leader RNA (SL RNA) in trans-splicing in Caenorhabditis elegans has been studied through a combination of in vitro mutagenesis and in vivo complementation of rrs-1 mutant nematodes, which lack endogenous SL1 RNA. Three classes of mutant SL1 RNAs have been found-those that rescue the lethal phenotyp...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.95.8.4235
更新日期:1998-04-14 00:00:00
abstract::Pituitary ablation (hypophysectomy) in rats was previously reported to cause a precipitous change in the relative abundance of two alternative splice variants of the "BK"- or "Maxi K"-encoding Slo gene in adrenal chromaffin cells. Inclusion of the optional "STREX" exon (STRess axis-regulated EXon) in a C-terminal spli...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.112619799
更新日期:2002-05-28 00:00:00
abstract::Mechanism of enzymatic conversion of a fatty acid to the corresponding alkane by the loss of the carboxyl carbon was investigated with particulate preparations from Pisum sativum. A heavy particulate preparation (sp. gr., 1.30 g/cm3) isolated by two density-gradient centrifugation steps catalyzed conversion of octadec...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.81.21.6613
更新日期:1984-11-01 00:00:00
abstract::Type I (IFN-alpha/beta) and type III (IFN-lambdas) IFNs are important components of the host antiviral response. Although type III IFNs possess intrinsic antiviral activity similar to that of type I IFNs, they signal through a specific unique receptor complex, and their functional importance for antiviral resistance i...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0610352104
更新日期:2007-06-05 00:00:00
abstract::Depending on the cellular context, BCL2-like proteins promote mitochondrial fusion or fission. What determines which of these two opposing processes they promote has so far been unknown. Furthermore, the mechanisms through which BCL2-like proteins affect mitochondrial dynamics remain to be fully understood. The BCL2-l...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1103218108
更新日期:2011-10-11 00:00:00
abstract::beta-Endorphin, an opiate-like peptide, has potent antinociceptive properties when it is administered directly into the brain and assayed in the the tail-flick, hot-plate, and writhing tests in mice and in the wet shake test in rats. On a molar basis, beta-endorphin is 18 to 33 times more potent than morphine and its ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.73.8.2895
更新日期:1976-08-01 00:00:00
abstract::The effect of Zn2+ on a voltage-dependent, transient potassium current (IA) in acutely dissociated neurons from the suprachiasmatic nucleus was studied with the whole-cell patch-clamp technique. At micromolar concentrations, Zn2+ markedly potentiated IA activated from a holding potential of -60 mV, which is the restin...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.90.24.11806
更新日期:1993-12-15 00:00:00
abstract::Antibodies are created and refined by somatic evolution in B cell populations, which endows the human immune system with the ability to recognize and eliminate diverse pathogens. However, the evolutionary processes that sculpt antibody repertoires remain poorly understood. Here, using an unbiased repertoire-scale appr...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1814213116
更新日期:2019-01-22 00:00:00
abstract::Alcoholism causes serious neurologic disease that may be due, in part, to the ability of ethanol to interact with neural cell membranes and change neuronal function. Adenosine receptors are membrane-bound proteins that appear to mediate some of the effects of ethanol in the brain. Human lymphocytes also have adenosine...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.84.5.1413
更新日期:1987-03-01 00:00:00
abstract::Inadequate resolution is the principal limitation of radiocarbon dating. However, recent work has shown that exact-year precision is attainable if use can be made of past increases in atmospheric radiocarbon concentration or so-called Miyake events. Here, this nascent method is applied to an archaeological site of pre...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1921301117
更新日期:2020-06-23 00:00:00
abstract::Recent studies have shown that genes involved in oxidative phosphorylation (OXPHOS) exhibit reduced expression in skeletal muscle of diabetic and prediabetic humans. Moreover, these changes may be mediated by the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alph...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0401401101
更新日期:2004-04-27 00:00:00
abstract::Somatic crossing-over was used in heterozygous Drosophila melanogaster to effect clonal homozygosity for three mutants (h, Hw, ac). In these mutants, one type of process, chaetae, replaces another type, trichomes, in specific patterns on the adult fly. Heterozygous individuals were irradiated at different larval or pu...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.68.9.2222
更新日期:1971-09-01 00:00:00
abstract::Monoclonal antibodies against the porcine 1,25-dihydroxyvitamin D3 receptor were immobilized on Sepharose CL-4B and used to obtain a highly purified 1,25-dihydroxyvitamin D3 receptor fraction with a 45% recovery of the 1,25-dihydroxyvitamin D3 binding capacity. The porcine receptor was purified to homogeneity by prepa...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.85.8.2454
更新日期:1988-04-01 00:00:00
abstract::A fundamental property of ecosystems is a tradeoff between the number and size of habitats: as the number of habitats within a fixed area increases, the average area per habitat must decrease. This tradeoff is termed the "area-heterogeneity tradeoff." Theoretical models suggest that the reduction in habitat sizes unde...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1911540117
更新日期:2020-03-03 00:00:00
abstract::Stepwise, synthetic alteration of oxytocin, guided by conformational and enzymological considerations, has led to analogs with specifically modified activity profiles and resistance to enzymatic inactivation. General requirements for the design of peptides with therapeutic value are discussed. ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.71.5.1901
更新日期:1974-05-01 00:00:00
abstract::We have previously linked aging, carcinogenesis, and de novo methylation within the promoter of the estrogen receptor (ER) gene in human colon. We now examine the dynamics of this process for the imprinted gene for insulin-like growth factor II (IGF2). In young individuals, the P2-4 promoters of IGF2 are methylated ex...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.93.21.11757
更新日期:1996-10-15 00:00:00