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  • 1
    Online Resource
    Online Resource
    Albumin mediates the transcytosis of myeloperoxidase by means of caveolae in endothelial cells
    Proceedings of the National Academy of Sciences ; 2004
    In:  Proceedings of the National Academy of Sciences Vol. 101, No. 20 ( 2004-05-18), p. 7699-7704
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 101, No. 20 ( 2004-05-18), p. 7699-7704
    Abstract: Myeloperoxidase (MPO), the phagocyte hemoprotein involved in neutrophil host defense and consuming nitric oxide ( • NO), induces the nitration of extracellular matrix proteins and tissue remodeling subsequent to its transcytosis across the endothelial barrier. We addressed the role of an interaction of MPO with albumin as a requirement for MPO transport across the endothelium. Matrix-assisted laser desorption/ionization MS analysis of 80- and 60-kDa proteins purified from human lung tissue [with a human serum albumin (HSA)-affinity column] identified these albumin-binding proteins as MPO and MPO-heavy chain. A peptide corresponding to the MPO-heavy chain residues 425–454 demonstrated high-affinity binding to HSA. Replacement of the positively charged residues, R and K with G, prevented the binding of HSA to the peptide. We observed that albumin increased the binding of 125 I-MPO to lung microvascular endothelial cells by 2-fold and the rate of transendothelial flux of 125 I-MPO in cultured monolayers and intact vessels. Disruption of caveolae with cyclodextrin prevented the albumin-induced increase in transendothelial flux of 125 I-MPO. We also observed by confocal imaging that albumin induced the rapid internalization of MPO and its colocalization with albumin-labeled vesicles. MPO colocalized with the caveolae markers cholera toxin subunit B and caveolin 1 in the endocytosed vesicles. Thus, transcytosis of MPO by caveolae induced by its charge-dependent interaction with albumin is an important means of delivering MPO to the subendothelial space. Albumin-mediated transport of MPO may thereby regulate NO bioavailability and formation of NO-derived oxidants in the vessel wall.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0401712101
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2004
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    detail.hit.zdb_id: 1461794-8
    SSG: 11
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  • 2
    Online Resource
    Online Resource
    AG10 inhibits amyloidogenesis and cellular toxicity of the familial amyloid cardiomyopathy-associated V122I transthyretin
    Proceedings of the National Academy of Sciences ; 2013
    In:  Proceedings of the National Academy of Sciences Vol. 110, No. 24 ( 2013-06-11), p. 9992-9997
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 110, No. 24 ( 2013-06-11), p. 9992-9997
    Abstract: The misassembly of soluble proteins into toxic aggregates, including amyloid fibrils, underlies a large number of human degenerative diseases. Cardiac amyloidoses, which are most commonly caused by aggregation of Ig light chains or transthyretin (TTR) in the cardiac interstitium and conducting system, represent an important and often underdiagnosed cause of heart failure. Two types of TTR-associated amyloid cardiomyopathies are clinically important. The Val122Ile (V122I) mutation, which alters the kinetic stability of TTR and affects 3% to 4% of African American subjects, can lead to development of familial amyloid cardiomyopathy. In addition, aggregation of WT TTR in individuals older than age 65 y causes senile systemic amyloidosis. TTR-mediated amyloid cardiomyopathies are chronic and progressive conditions that lead to arrhythmias, biventricular heart failure, and death. As no Food and Drug Administration-approved drugs are currently available for treatment of these diseases, the development of therapeutic agents that prevent TTR-mediated cardiotoxicity is desired. Here, we report the development of AG10, a potent and selective kinetic stabilizer of TTR. AG10 prevents dissociation of V122I-TTR in serum samples obtained from patients with familial amyloid cardiomyopathy. In contrast to other TTR stabilizers currently in clinical trials, AG10 stabilizes V122I- and WT-TTR equally well and also exceeds their efficacy to stabilize WT and mutant TTR in whole serum. Crystallographic studies of AG10 bound to V122I-TTR give valuable insights into how AG10 achieves such effective kinetic stabilization of TTR, which will also aid in designing better TTR stabilizers. The oral bioavailability of AG10, combined with additional desirable drug-like features, makes it a very promising candidate to treat TTR amyloid cardiomyopathy.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1300761110
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2013
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 3
    Online Resource
    Online Resource
    The butterfly plant arms-race escalated by gene and genome duplications
    Proceedings of the National Academy of Sciences ; 2015
    In:  Proceedings of the National Academy of Sciences Vol. 112, No. 27 ( 2015-07-07), p. 8362-8366
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 112, No. 27 ( 2015-07-07), p. 8362-8366
    Abstract: Coevolutionary interactions are thought to have spurred the evolution of key innovations and driven the diversification of much of life on Earth. However, the genetic and evolutionary basis of the innovations that facilitate such interactions remains poorly understood. We examined the coevolutionary interactions between plants (Brassicales) and butterflies (Pieridae), and uncovered evidence for an escalating evolutionary arms-race. Although gradual changes in trait complexity appear to have been facilitated by allelic turnover, key innovations are associated with gene and genome duplications. Furthermore, we show that the origins of both chemical defenses and of molecular counter adaptations were associated with shifts in diversification rates during the arms-race. These findings provide an important connection between the origins of biodiversity, coevolution, and the role of gene and genome duplications as a substrate for novel traits.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1503926112
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2015
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 4
    Online Resource
    Online Resource
    Nucleotide excision repair deficiency is intrinsic in sporadic stage I breast cancer
    Proceedings of the National Academy of Sciences ; 2010
    In:  Proceedings of the National Academy of Sciences Vol. 107, No. 50 ( 2010-12-14), p. 21725-21730
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 107, No. 50 ( 2010-12-14), p. 21725-21730
    Abstract: The molecular etiology of breast cancer has proven to be remarkably complex. Most individual oncogenes are disregulated in only approximately 30% of breast tumors, indicating that either very few molecular alterations are common to the majority of breast cancers, or that they have not yet been identified. In striking contrast, we now show that 19 of 19 stage I breast tumors tested with the functional unscheduled DNA synthesis assay exhibited a significant deficiency of DNA nucleotide excision repair (NER) capacity relative to normal epithelial tissue from disease-free controls ( n = 23). Loss of DNA repair capacity, including the complex, damage-comprehensive NER pathway, results in genomic instability, a hallmark of carcinogenesis. By microarray analysis, mRNA expression levels for 20 canonical NER genes were reduced in representative tumor samples versus normal. Significant reductions were observed in 19 of these genes analyzed by the more sensitive method of RNase protection. These results were confirmed at the protein level for five NER gene products. Taken together, these data suggest that NER deficiency may play an important role in the etiology of sporadic breast cancer, and that early-stage breast cancer may be intrinsically susceptible to genotoxic chemotherapeutic agents, such as cis -platinum, whose damage is remediated by NER. In addition, reduced NER capacity, or reduced expression of NER genes, could provide a basis for the development of biomarkers for the identification of tumorigenic breast epithelium.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0914772107
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2010
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Location Call Number Limitation Availability
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  • 5
    Online Resource
    Online Resource
    The tumorigenic potential and cell growth characteristics of p53-deficient cells are equivalent in the presence or absence of Mdm2
    Proceedings of the National Academy of Sciences ; 1996
    In:  Proceedings of the National Academy of Sciences Vol. 93, No. 24 ( 1996-11-26), p. 14106-14111
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 93, No. 24 ( 1996-11-26), p. 14106-14111
    Abstract: The Mdm2 oncoprotein forms a complex with the p53 tumor suppressor protein and inhibits p53-mediated regulation of heterologous gene expression. Recently, Mdm2 has been found to bind several other proteins that function to regulate cell cycle progression, including the E2F-1/DP1 transcription factor complex and the retinoblastoma tumor-suppressor protein. To determine whether Mdm2 plays a role in cell cycle control or tumorigenesis that is distinct from its ability to modulate p53 function, we have examined and compared both the in vitro growth characteristics of p53-deficient and Mdm2/p53-deficient fibroblasts, and the rate and spectrum of tumor formation in p53-deficient and Mdm2/p53-deficient mice. We find no difference between p53-deficient fibroblasts and Mdm2/p53-deficient fibroblasts either in their rate of proliferation in culture or in their survival frequency when treated with various genotoxic agents. Cell cycle studies indicate no difference in the ability of the two cell populations to enter S phase when treated with DNA-damaging agents or nucleotide antimetabolites, and p53-deficient fibroblasts and Mdm2/p53-deficient fibroblasts exhibit the same rate of spontaneous immortalization following long-term passage in culture. Finally, p53-deficient mice and Mdm2/p53-deficient mice display the same incidence and spectrum of spontaneous tumor formation in vivo . These results demonstrate that deletion of Mdm2 has no additional effect on cell proliferation, cell cycle control, or tumorigenesis when p53 is absent.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.93.24.14106
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 1996
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Location Call Number Limitation Availability
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