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81.
Berezov A Chen J Liu Q Zhang HT Greene MI Murali R 《The Journal of biological chemistry》2002,277(31):28330-28339
Members of the erbB family receptor tyrosine kinases (erbB1, erbB2, erbB3, and erbB4) are overexpressed in a variety of human cancers and represent important targets for the structure-based drug design. Homo- and heterodimerization (oligomerization) of the erbB receptors are known to be critical events for receptor signaling. To block receptor self-associations, we have designed a series of peptides derived from potential dimerization surfaces in the extracellular subdomain IV of the erbB receptors (erbB peptides). In surface plasmon resonance (BIAcore) studies, the designed peptides have been shown to selectively bind to the erbB receptor ectodomains and isolated subdomain IV of erbB2 with submicromolar affinities and to inhibit heregulin-induced interactions of erbB3 with different erbB receptors. A dose-dependent inhibition of native erbB receptor dimerization by the erbB peptides has been observed in 32D cell lines transfected with different combinations of erbB receptors. The peptides effectively inhibited growth of two types of transformed cells overexpressing different erbB receptors, T6-17 and 32D, in standard MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and cell viability assays. The study identifies distinct loops within the membrane-proximal part of the subdomain IV as potential receptor-receptor interaction sites for the erbB receptors and demonstrates the possibility of disabling receptor activity by structure-based targeting of the dimerization interfaces. Molecular models for possible arrangement of the erbB1.EGF complex, consistent with the involvement of subdomain IV in inter-receptor interactions, are proposed. Small dimerization inhibitors described herein can be useful as probes to elucidate different erbB signaling pathways and may be developed as therapeutic agents. 相似文献
82.
A multi-channel sandwich microgravimetric immunoassay (sMIA), using the quartz crystal microbalance (QCM) principle, has been developed to quantify low molecular weight substances in standard solutions. An antigen is sandwiched between two antigen-specific antibodies: the first antibody is coated on the quartz crystal surface and the second antibody is used for the detection of analyte. The concentration of low molecular weight antigen (insulin was used in this study, M
r6000 Da) was correlated with the shift of resonant frequency of QCM system before and after second antibody binding to insulin. The developed assay is highly specific showing low cross-reactivity, and is sensitive to approx. 1 ng insulin ml–1 with a linear response for insulin from 10 g ml–1 to 10 ng ml–1 in standard solutions. The technique may also be applied for the detection of other small biomolecules. 相似文献
83.
Robinson FL Whitehurst AW Raman M Cobb MH 《The Journal of biological chemistry》2002,277(17):14844-14852
Extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2) are essential components of pathways through which signals received at membrane receptors are converted into specific changes in protein function and gene expression. As with other members of the mitogen-activated protein (MAP) kinase family, ERK1 and ERK2 are activated by phosphorylations catalyzed by dual-specificity protein kinases known as MAP/ERK kinases (MEKs). MEKs exhibit stringent specificity for individual MAP kinases. Indeed, MEK1 and MEK2 are the only known activators of ERK1 and ERK2. ERK2 small middle dotMEK1/2 complexes can be detected in vitro and in vivo. The biochemical nature of such complexes and their role in MAP kinase signaling are under investigation. This report describes the use of a yeast two-hybrid screen to identify point mutations in ERK2 that impair its interaction with MEK1/2, yet do not alter its interactions with other proteins. ERK2 residues identified in this screen are on the surface of the C-terminal domain of the kinase, either within or immediately preceding alpha-helix G, or within the MAP kinase insert. Some mutations identified in this manner impaired the two-hybrid interaction of ERK2 with both MEK1 and MEK2, whereas others had a predominant effect on the interaction with either MEK1 or MEK2. Mutant ERK2 proteins displayed reduced activation in HEK293 cells following epidermal growth factor treatment, consistent with their impaired interaction with MEK1/2. However, ERK2 proteins containing MEK-specific mutations retained kinase activity, and were similar to wild type ERK2 in their activation following overexpression of constitutively active MEK1. Unlike wild type ERK2, proteins containing MEK-specific point mutations were constitutively localized in the nucleus, even in the presence of overexpressed MEK1. These data suggest an essential role for the MAP kinase insert and residues within or just preceding alpha-helix G in the interaction of ERK2 with MEK1/2. 相似文献
84.
Agrawal R Chandrashekhar R Mishra AK Ramadevi J Sharma Y Aggarwal RK 《Journal of biosciences》2002,27(3):251-259
τ-Crystallin is a taxon-specific structural protein found in eye lenses. We present here the cloning and sequencing of complete
τ-crystallin cDNA from the embryonic lens ofCrocodylus palustris and establish it to be identical to the α-enolase gene from non-lenticular tissues. Quantitatively, the τ-crystallin was
found to be the least abundant crystallin of the crocodilian embryonic lenses. Crocodile τ-crystallin cDNA was isolated by
RT-PCR using primers designed from the only other reported sequence from duck and completed by 5′- and 3′-rapid amplification
of cDNA ends (RACE) using crocodile gene specific primers designed in the study. The complete τ-crystallin cDNA of crocodile
comprises 1305 bp long ORF and 92 and 409 bp long untranslated 5′- and 3′-ends respectively. Further, it was found to be identical
to its putative counterpart enzyme α-enolase, from brain, heart and gonad, suggesting both to be the product of the same gene.
The study thus provides the first report on cDNA sequence of τ-crystallin from a reptilian species and also re-confirms it
to be an example of the phenomenon of gene sharing as was demonstrated earlier in the case of peking duck. Moreover, the gene
lineage reconstruction analysis helps our understanding of the evolution of crocodilians and avian species. 相似文献
85.
AP2 adaptor complex-dependent internalization of CD5: differential regulation in T and B cells 总被引:1,自引:0,他引:1
Lu X Axtell RC Collawn JF Gibson A Justement LB Raman C 《Journal of immunology (Baltimore, Md. : 1950)》2002,168(11):5612-5620
CD5 is a key regulator of Ag receptor-mediated activation, selection, and differentiation in both T and B cells. Accumulating evidence indicates that lymphocyte activation and selection are sensitive to variations in levels of CD5 on the cell surface. We now show that CD5 expression on the surface of B and T cells is regulated posttranslationally by direct interaction with the mu(2) subunit of the AP2 adaptor complex that links transmembrane proteins to clathrin-coated pits. CD5 is rapidly internalized from the cell surface in lymphoid cell lines, mature splenic T and B cells, and peritoneal CD5(+) B cells following monovalent or bivalent ligation of the receptor. We mapped the mu(2) subunit binding site on CD5 to Y(429) and determined that the integrity of this site was necessary for CD5 internalization. Cross-linking of the Ag receptor with intact Abs inhibited CD5 internalization in B cells, but had the opposite effect in T cells. However, if F(ab')(2) Abs were used to stimulate the Ag receptor in B cells, the effect on CD5 internalization was now similar to that observed in T cells, indicating that signals through the Ag receptor and FcR regulate CD5 endocytosis in B cells. This was confirmed using an FcgammaRIIB1-deficient B cell line. The ability to differentially alter posttranslational CD5 expression in T and B cells is likely to be key in regulation of Ag receptor signaling and generation of tolerance in T and B lymphocytes. 相似文献
86.
87.
In an earlier report on fungal protease (F-prot)-fatty acid biocomposite film formation [Gole et al. Anal. Chem. 2000, 72, 4301], it was observed that the biocatalytic activity of the immobilized enzyme was comparable to that of the free enzyme in solution. However, a somewhat negative aspect of the protocol was the steady loss in activity during reuse and storage of the biocomposite film. In this paper, we address the latter issues and demonstrate successful attempts toward the realization of efficient biocomposite films with enhanced biological activity, temporal stability, and excellent reusability. The improved performance of the F-prot-stearic acid biocomposite is accomplished by preordering the fatty acid film by incorporation of Pb(2+) ions into the lipid matrix prior to enzyme immobilization. The lead cation induces lamellar ordering in the lipid film and thus facilitates diffusion of the F-prot molecules into the lipid matrix and accessibility of the substrate molecules (hemoglobin, Hb) to the entrapped F-prot enzyme molecules. The preordering consequently leads to effective control of the "mass transport" problem and might be responsible for the enhanced biological activity ( approximately 36%) of the enzyme molecules in the biocomposite in comparison with the free enzyme in solution, as well the excellent reusability of the composite film. In addition to biocatalytic activity measurements, the formation and characterization of the F-prot-lead stearate biocomposite films was done by quartz crystal microgravimetry and X-ray diffraction. 相似文献
88.
Xavier S Yamada K Samuni AM Samuni A DeGraff W Krishna MC Mitchell JB 《Biochimica et biophysica acta》2002,1573(2):109-120
Modulation of radiation- and metal ion-catalyzed oxidative-induced damage using plasmid DNA, genomic DNA, and cell survival, by three nitroxides and their corresponding hydroxylamines, were examined. The antioxidant property of each compound was independently determined by reacting supercoiled DNA with copper II/1,10-phenanthroline complex fueled by the products of hypoxanthine/xanthine oxidase (HX/XO) and noting the protective effect as assessed by agarose gel electrophoresis. The nitroxides and their corresponding hydroxylamines protected approximately to the same degree (33-47% relaxed form) when compared to 76.7% relaxed form in the absence of protectors. Likewise, protection by both the nitroxide and corresponding hydroxylamine were observed for Chinese hamster V79 cells exposed to hydrogen peroxide. In contrast, when plasmid DNA damage was induced by ionizing radiation (100 Gy), only nitroxides (10 mM) provide protection (32.4-38.5% relaxed form) when compared to radiation alone or in the presence of hydroxylamines (10 mM) (79.8% relaxed form). Nitroxide protection was concentration dependent. Radiation cell survival studies and DNA double-strand break (DBS) assessment (pulse field electrophoresis) showed that only the nitroxide protected or prevented damage, respectively. Collectively, the results show that nitroxides and hydroxylamines protect equally against the damage mediated by oxidants generated by the metal ion-catalyzed Haber-Weiss reaction, but only nitroxides protect against radiation damage, suggesting that nitroxides may more readily react with intermediate radical species produced by radiation than hydroxylamines. 相似文献
89.
An information theoretic approach for analyzing temporal patterns of gene expression 总被引:4,自引:0,他引:4
MOTIVATION: Arrays allow measurements of the expression levels of thousands of mRNAs to be made simultaneously. The resulting data sets are information rich but require extensive mining to enhance their usefulness. Information theoretic methods are capable of assessing similarities and dissimilarities between data distributions and may be suited to the analysis of gene expression experiments. The purpose of this study was to investigate information theoretic data mining approaches to discover temporal patterns of gene expression from array-derived gene expression data. RESULTS: The Kullback-Leibler divergence, an information-theoretic distance that measures the relative dissimilarity between two data distribution profiles, was used in conjunction with an unsupervised self-organizing map algorithm. Two published, array-derived gene expression data sets were analyzed. The patterns obtained with the KL clustering method were found to be superior to those obtained with the hierarchical clustering algorithm using the Pearson correlation distance measure. The biological significance of the results was also examined. AVAILABILITY: Software code is available by request from the authors. All programs were written in ANSI C and Matlab (Mathworks Inc., Natick, MA). 相似文献
90.
Hurwitz RL Chévez-Barrios P Boniuk M Chintagumpala M Hurwitz MY 《Expert reviews in molecular medicine》2003,5(1):1-14
Retinoblastoma (Rb) is the most common primary ocular malignancy of children and is caused by a mutation in the gene RB1. Approximately 40% of cases are associated with one or more constitutional mutations, and are therefore heritable, whereas the other 60% are sporadic. Rb is exclusively found in young children. In some cases, Rb tumours metastasise to extraocular organs including bone, lung and brain. Although there is no effective treatment for metastatic disease, non-metastatic cases can be cured by removal of the eye(enucleation). Newer treatment strategies emphasise salvaging the affected eye whenever possible. Animal models of Rb have been developed with xenograft and transgenic techniques. Each model has both strengths and weaknesses for exploring the mechanisms of disease development and progression and the efficacy of new treatment strategies. 相似文献