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Proceedings of the National Academy of Sciences of... 110건

  1. [해외논문]   Intermediates can accelerate protein folding.  

    Wagner, C , Kiefhaber, T
    Proceedings of the National Academy of Sciences of the United States of America v.96 no.12 ,pp. 6716 - 6721 , 1999 , 0027-8424 ,

    초록

    The effect of intermediates on the rate of protein folding is explored by applying Kramers' theory of diffusive barrier crossing in the high friction limit. Intermediates are represented as local minima in the transition barrier. We observe that very large or very small additional barriers created by the intermediates slow down the folding process. The rate of folding markedly increases, however, when the additional barriers become >1 kBT but leave the overall barrier height unchanged. This rate-enhancing effect is caused by a favorable entropic contribution to the free energy of activation, and it increases with the number of intermediates up to a limiting value. From these calculations, we conclude that optimized transition barriers should contain partially folded high energy intermediates.

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  2. [해외논문]   Clathrin-coated vesicles bearing GAIP possess GTPase-activating protein activity in vitro.  

    Fischer, T , Elenko, E , McCaffery, J M , DeVries, L , Farquhar, M G
    Proceedings of the National Academy of Sciences of the United States of America v.96 no.12 ,pp. 6722 - 6727 , 1999 , 0027-8424 ,

    초록

    Galpha-interacting protein (GAIP) is a member of the RGS (regulators of G protein signaling) family, which serve as GAPs (GTPase-activating proteins) for Galpha subunits. Previously, we demonstrated that GAIP is localized on clathrin-coated vesicles (CCVs). Here, we tested whether GAIP-enriched vesicles could accelerate the GTPase activity of Galphai proteins. A rat liver fraction containing vesicular carriers (CV2) was enriched (4.5x) for GAIP by quantitative immunoblotting, and GAIP was detected on some of the vesicles in the CV2 fraction by immunoelectron microscopy. When liver fractions were added to recombinant Galphai3 and tested for GAP activity, only the CV2 fraction contained GAP activity. Increasing amounts of CV2 increased the activity, whereas immunodepletion of the CV2 fraction with an antibody against the C terminus of GAIP decreased GAP activity. CCV fractions were prepared from rat liver by using a protocol that maintains the clathrin coats. GAIP was enriched in these fractions and was detected on CCVs by immunogold labeling. Addition of increasing amounts of CCV to recombinant Galphai3 protein increased the GTPase activity. We conclude that CCVs possess GAP activity for Galphai3 and that membrane-associated GAIP is capable of interacting with Galphai3. The reconstitution of the interaction between a heterotrimeric G protein and GAIP on CCVs provides biochemical evidence for a model whereby the G protein and its GAP are compartmentalized on different membranes and come into contact at the time of vesicle fusion. Alternatively, they may be located on the same membrane and segregate at the time of vesicle budding.

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  3. [해외논문]   Signaling via 1 integrins and mitogen-activated protein kinase determines human epidermal stem cell fate in vitro  

    Zhu, A. J. , Haase, I. , Watt, F. M.
    Proceedings of the National Academy of Sciences of the United States of America v.96 no.12 ,pp. 6728 - 6733 , 1999 , 0027-8424 ,

    초록

    Galpha-interacting protein (GAIP) is a member of the RGS (regulators of G protein signaling) family, which serve as GAPs (GTPase-activating proteins) for Galpha subunits. Previously, we demonstrated that GAIP is localized on clathrin-coated vesicles (CCVs). Here, we tested whether GAIP-enriched vesicles could accelerate the GTPase activity of Galphai proteins. A rat liver fraction containing vesicular carriers (CV2) was enriched (4.5x) for GAIP by quantitative immunoblotting, and GAIP was detected on some of the vesicles in the CV2 fraction by immunoelectron microscopy. When liver fractions were added to recombinant Galphai3 and tested for GAP activity, only the CV2 fraction contained GAP activity. Increasing amounts of CV2 increased the activity, whereas immunodepletion of the CV2 fraction with an antibody against the C terminus of GAIP decreased GAP activity. CCV fractions were prepared from rat liver by using a protocol that maintains the clathrin coats. GAIP was enriched in these fractions and was detected on CCVs by immunogold labeling. Addition of increasing amounts of CCV to recombinant Galphai3 protein increased the GTPase activity. We conclude that CCVs possess GAP activity for Galphai3 and that membrane-associated GAIP is capable of interacting with Galphai3. The reconstitution of the interaction between a heterotrimeric G protein and GAIP on CCVs provides biochemical evidence for a model whereby the G protein and its GAP are compartmentalized on different membranes and come into contact at the time of vesicle fusion. Alternatively, they may be located on the same membrane and segregate at the time of vesicle budding.

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  4. [해외논문]   Signaling via beta1 integrins and mitogen-activated protein kinase determines human epidermal stem cell fate in vitro.  

    Zhu, A J , Haase, I , Watt, F M
    Proceedings of the National Academy of Sciences of the United States of America v.96 no.12 ,pp. 6728 - 6733 , 1999 , 0027-8424 ,

    초록

    Human epidermal stem cells express higher levels of beta1 integrins and are more adhesive than keratinocytes that are destined to differentiate. To investigate whether high beta1 integrin expression and adhesiveness are essential for maintaining keratinocytes in the stem cell compartment, we introduced a dominant-negative beta1 integrin mutant, CD8beta1, into cultured human keratinocytes, thereby interfering with beta1 integrin function. Surface beta1 integrin levels, adhesiveness, and mitogen-activated protein (MAP) kinase activation on fibronectin were reduced, and exit from the stem cell compartment was stimulated. Adhesiveness and proliferative potential were restored by overexpressing wild-type beta1 integrin or by constitutive MAP kinase activation. Conversely, a dominant-negative MAP kinase kinase 1 mutant decreased adhesiveness and stem cell number in the absence of CD8beta1. MAP kinase activation by alpha6beta4-mediated adhesion and mitogens was normal in CD8beta1 cells, and constitutive MAP kinase activation did not affect adhesion and proliferation of control keratinocytes. We conclude that beta1 integrins and MAP kinase cooperate to maintain the epidermal stem cell compartment in vitro.

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    회원님의 원문열람 권한에 따라 열람이 불가능 할 수 있으며 권한이 없는 경우 해당 사이트의 정책에 따라 회원가입 및 유료구매가 필요할 수 있습니다.이동하는 사이트에서의 모든 정보이용은 NDSL과 무관합니다.

    NDSL에서는 해당 원문을 복사서비스하고 있습니다. 아래의 원문복사신청 또는 장바구니담기를 통하여 원문복사서비스 이용이 가능합니다.

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  5. [해외논문]   A dominant-negative pleiotrophin mutant introduced by homologous recombination leads to germ-cell apoptosis in male mice.  

    Zhang, N , Yeh, H J , Zhong, R , Li, Y S , Deuel, T F
    Proceedings of the National Academy of Sciences of the United States of America v.96 no.12 ,pp. 6734 - 6738 , 1999 , 0027-8424 ,

    초록

    Pleiotrophin (PTN) is an 18-kDa heparin-binding secretory growth/differentiation factor for different cell types. Its gene is differentially expressed in both mesenchyme and central nervous system during development and highly expressed in a number of different human tumors. Recently, a PTN mutant was found to act as a dominant-negative effector of PTN signaling. We have now used homologous recombination to introduce the dominant-negative PTN mutant into embryonic stem cells to generate chimeric mice. All highly chimeric male mice with germinal epithelium exclusively derived from embryonic stem cells with the heterologous PTN mutation were sterile. Their testes were uniformly atrophic, and the spermatocytes were strikingly apoptotic at all stages of development. The results support a central role of PTN signaling in normal spermatogenesis and suggest that interruption of PTN signaling may lead to sterility in males.

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    NDSL에서는 해당 원문을 복사서비스하고 있습니다. 아래의 원문복사신청 또는 장바구니담기를 통하여 원문복사서비스 이용이 가능합니다.

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  6. [해외논문]   A Crm1p-independent nuclear export path for the mRNA-associated protein, Npl3p/Mtr13p.  

    Liu, Y , Guo, W , Tartakoff, P Y , Tartakoff, A M
    Proceedings of the National Academy of Sciences of the United States of America v.96 no.12 ,pp. 6739 - 6744 , 1999 , 0027-8424 ,

    초록

    mRNA export involves association of mRNAs with nucleoplasmic proteins, delivery to the nuclear pore complex, translocation to the cytoplasm, and reimport of recycling components. Many yeast mutants inhibit mRNA export, but there is little information concerning the RNA carriers and steps of transport that they affect. The hnRNP/serine-arginine-rich-like protein, Npl3p/Mtr13p, binds poly(A)+ RNA and shuttles between the nucleus and cytoplasm. Its export accelerates on inhibition of RNA synthesis. In vivo tests show that its export requires two proteins with putative leucine-rich nuclear export signals: Gle1p, Mex67p, and several additional nuclear and nuclear pore complex-associated proteins. Surprisingly, a nonnuclear pool of an import factor (the importin alpha homologue, Srp1p) is also required. Changes in the methylation status of Npl3p do not correlate with its nucleocytoplasmic distribution. A crm1 mutant that inhibits export of proteins with leucine-rich nuclear export signals and mRNAs does not inhibit Npl3p export. Moreover, several proteins needed for Npl3p export are not needed for export of a typical Crm1p cargo. Thus, Npl3p export requires only a subset of proteins implicated in mRNA export, suggesting that more than one mRNA export path exists. A distinct group of mutants, including a mutation of a member of the importin beta superfamily, inhibits Npl3p reimport from the cytoplasm.

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    NDSL에서는 해당 원문을 복사서비스하고 있습니다. 아래의 원문복사신청 또는 장바구니담기를 통하여 원문복사서비스 이용이 가능합니다.

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  7. [해외논문]   Broad patterns of gene expression revealed by clustering analysis of tumor and normal colon tissues probed by oligonucleotide arrays.  

    Alon, U , Barkai, N , Notterman, D A , Gish, K , Ybarra, S , Mack, D , Levine, A J
    Proceedings of the National Academy of Sciences of the United States of America v.96 no.12 ,pp. 6745 - 6750 , 1999 , 0027-8424 ,

    초록

    Oligonucleotide arrays can provide a broad picture of the state of the cell, by monitoring the expression level of thousands of genes at the same time. It is of interest to develop techniques for extracting useful information from the resulting data sets. Here we report the application of a two-way clustering method for analyzing a data set consisting of the expression patterns of different cell types. Gene expression in 40 tumor and 22 normal colon tissue samples was analyzed with an Affymetrix oligonucleotide array complementary to more than 6,500 human genes. An efficient two-way clustering algorithm was applied to both the genes and the tissues, revealing broad coherent patterns that suggest a high degree of organization underlying gene expression in these tissues. Coregulated families of genes clustered together, as demonstrated for the ribosomal proteins. Clustering also separated cancerous from noncancerous tissue and cell lines from in vivo tissues on the basis of subtle distributed patterns of genes even when expression of individual genes varied only slightly between the tissues. Two-way clustering thus may be of use both in classifying genes into functional groups and in classifying tissues based on gene expression.

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    NDSL에서는 해당 원문을 복사서비스하고 있습니다. 아래의 원문복사신청 또는 장바구니담기를 통하여 원문복사서비스 이용이 가능합니다.

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  8. [해외논문]   Ultraviolet A radiation induces immediate release of iron in human primary skin fibroblasts: the role of ferritin.  

    Pourzand, C , Watkin, R D , Brown, J E , Tyrrell, R M
    Proceedings of the National Academy of Sciences of the United States of America v.96 no.12 ,pp. 6751 - 6756 , 1999 , 0027-8424 ,

    초록

    In mammalian cells, the level of the iron-storage protein ferritin (Ft) is tightly controlled by the iron-regulatory protein-1 (IRP-1) at the posttranscriptional level. This regulation prevents iron acting as a catalyst in reactions between reactive oxygen species and biomolecules. The ultraviolet A (UVA) radiation component of sunlight (320-400 nm) has been shown to be a source of oxidative stress to skin via generation of reactive oxygen species. We report here that the exposure of human primary skin fibroblasts, FEK4, to UVA radiation causes an immediate release of "free" iron in the cells via proteolysis of Ft. Within minutes of exposure to a range of doses of UVA at natural exposure levels, the binding activity of IRP-1, as well as Ft levels, decreases in a dose-dependent manner. This decrease coincides with a significant leakage of the lysosomal components into the cytosol. Stabilization of Ft molecules occurs only when cells are pretreated with lysosomal protease inhibitors after UVA treatment. We propose that the oxidative damage to lysosomes that leads to Ft degradation and the consequent rapid release of potentially harmful "free" iron to the cytosol might be a major factor in UVA-induced damage to the skin.

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  9. [해외논문]   Control of the low voltage-activated calcium channel of mouse sperm by egg ZP3 and by membrane hyperpolarization during capacitation.  

    Arnoult, C , Kazam, I G , Visconti, P E , Kopf, G S , Villaz, M , Florman, H M
    Proceedings of the National Academy of Sciences of the United States of America v.96 no.12 ,pp. 6757 - 6762 , 1999 , 0027-8424 ,

    초록

    Sperm adhesion to egg zonae pellucidae initiates sperm acrosome reactions, an exocytotic event that is an early step during fertilization. Previously, it was suggested that zona pellucida-evoked Ca2+ entry into sperm through low voltage-activated Ca2+ channels is an essential step in acrosome reactions, based on the inhibitory effects of Ca2+ channel antagonists. However, analysis of this channel is limited by the inability to apply electrophysiological methods directly to sperm. In this report, optical methods of determining membrane potential and internal Ca2+ levels were used to demonstrate that (i) contact with zonae pellucidae activates a transient Ca2+ response in sperm that has a time course and antagonist sensitivity anticipated of low voltage-activated Ca2+ channels; (ii) these channels are unavailable for opening in uncapacitated sperm because of voltage-dependent, steady state inactivation; (iii) membrane hyperpolarization during sperm capacitation is sufficient to recruit channels into a closed state, from which they are available for opening during fertilization; and (iv) channel conductance state may be a factor in determines the efficacy with which channel antagonists inhibit fertilization. This study provides evidence for the activation of sperm Ca2+ channels during gamete adhesion and offers a mechanism that may account for aspects of the regulation of sperm fertility during capacitation through the control of channel availability. Finally, these results suggest that channel conductance state may be a central feature in the design of channel antagonists that inhibit sperm function.

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  10. [해외논문]   Two distinct forms of the 64,000 Mr protein of the cleavage stimulation factor are expressed in mouse male germ cells.  

    Wallace, A M , Dass, B , Ravnik, S E , Tonk, V , Jenkins, N A , Gilbert, D J , Copeland, N G , MacDonald, C C
    Proceedings of the National Academy of Sciences of the United States of America v.96 no.12 ,pp. 6763 - 6768 , 1999 , 0027-8424 ,

    초록

    Polyadenylation in male germ cells differs from that in somatic cells. Many germ cell mRNAs do not contain the canonical AAUAAA in their 3' ends but are efficiently polyadenylated. To determine whether the 64,000 Mr protein of the cleavage stimulation factor (CstF-64) is altered in male germ cells, we examined its expression in mouse testis. In addition to the 64,000 Mr form, we found a related approximately 70,000 Mr protein that is abundant in testis, at low levels in brain, and undetectable in all other tissues examined. Expression of the approximately 70,000 Mr CstF-64 was limited to meiotic spermatocytes and postmeiotic spermatids in testis. In contrast, the 64,000 Mr form was absent from spermatocytes, suggesting that the testis-specific CstF-64 might control expression of meiosis-specific genes. To determine why the 64,000 Mr CstF-64 is not expressed in spermatocytes, we mapped its chromosomal location to the X chromosome in both mouse and human. CstF-64 may, therefore, be absent in spermatocytes because the X chromosome is inactivated during male meiosis. By extension, the testis-specific CstF-64 may be expressed from an autosomal homolog of the X chromosomal gene.

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