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A dynamic model for bilirubin binding to human serum albumin 总被引:1,自引:0,他引:1
Petersen CE Ha CE Harohalli K Feix JB Bhagavan NV 《The Journal of biological chemistry》2000,275(28):20985-20995
Site-directed mutagenesis of human serum albumin was used to study the role of various amino acid residues in bilirubin binding. A comparison of thermodynamic, proteolytic, and x-ray crystallographic data from previous studies allowed a small number of amino acid residues in subdomain 2A to be selected as targets for substitution. The following recombinant human serum albumin species were synthesized in the yeast species Pichia pastoris: K195M, K199M, F211V, W214L, R218M, R222M, H242V, R257M, and wild type human serum albumin. The affinity of bilirubin was measured by two independent methods and found to be similar for all human serum albumin species. Examination of the absorption and circular dichroism spectra of bilirubin bound to its high affinity site revealed dramatic differences between the conformations of bilirubin bound to the above human serum albumin species. The absorption and circular dichroism spectra of bilirubin bound to the above human serum albumin species in aqueous solutions saturated with chloroform were also examined. The effect of certain amino acid substitutions on the conformation of bound bilirubin was altered by the addition of chloroform. In total, the present study suggests a dynamic, unusually flexible high affinity binding site for bilirubin on human serum albumin. 相似文献
174.
Mullerian inhibiting substance inhibits breast cancer cell growth through an NFkappa B-mediated pathway 总被引:2,自引:0,他引:2
Segev DL Ha TU Tran TT Kenneally M Harkin P Jung M MacLaughlin DT Donahoe PK Maheswaran S 《The Journal of biological chemistry》2000,275(37):28371-28379
Müllerian inhibiting substance (MIS), a member of the transforming growth factor-beta superfamily, induces regression of the Müllerian duct in male embryos. In this report, we demonstrate MIS type II receptor expression in normal breast tissue and in human breast cancer cell lines, breast fibroadenoma, and ductal adenocarcinomas. MIS inhibited the growth of both estrogen receptor (ER)-positive T47D and ER-negative MDA-MB-231 breast cancer cell lines, suggesting a broader range of target tissues for MIS action. Inhibition of growth was manifested by an increase in the fraction of cells in the G(1) phase of the cell cycle and induction of apoptosis. Treatment of breast cancer cells with MIS activated the NFkappaB pathway and selectively up-regulated the immediate early gene IEX-1S, which, when overexpressed, inhibited breast cancer cell growth. Dominant negative IkappaBalpha expression ablated both MIS-mediated induction of IEX-1S and inhibition of growth, indicating that activation of the NFkappaB signaling pathway was required for these processes. These results identify the NFkappaB-mediated signaling pathway and a target gene for MIS action and suggest a putative role for the MIS ligand and its downstream interactors in the treatment of ER-positive as well as negative breast cancers. 相似文献
175.
Retinoic Acid and Its Geometrical Isomers Block Both Growth and Fusion of L6 Myoblasts by Modulating the Expression of Protein Kinase A 总被引:1,自引:0,他引:1
All-trans retinoic acid (RA) and its geometrical isomers, such as 9-cis RA, 13-cis RA, and 9,13-di-cis RA, strongly inhibited both growth and fusion of L6 myoblasts. However, illumination of white light diminished their inhibitory activity on membrane fusion with little effect on cell growth. During myogenic differentiation, the intracellular level of cAMP decreased whereas the total activity of protein kinase A as well as the protein level of its regulatory subunit I (RI) and catalytic subunit (C) increased. RAs raised the intracellular level of cAMP by over 3-fold, but decreased the total activity of protein kinase A. Like RAs, dibutyryl-cAMP inhibited myoblast fusion and reduced the expression of both RI and C subunits. These results suggest that RAs negatively modulate the differentiation of L6 myoblasts by increasing the intracellular level of cAMP, which may in turn down-regulate the expression of protein kinase A and hence its activity. 相似文献
176.
Dopamine D2 receptor (DRD2) is one of the five dopamine receptors with seven transmembrane domains that are coupled to the G protein. We have cloned and characterized the genomic and cDNA sequences of the canine DRD2 gene, which are 12.7 and 2.7 kb in size, respectively. The genomic DNA is composed of seven exons and six introns, encoding a 443 amino acid protein with 95% amino acid identity to other mammalian D2 receptors. A length polymorphism was detected in intron 3 of the receptor gene. We also characterized alternatively spliced forms of DRD2 cDNAs, DRD2L and DRD2S. They showed a higher level of expression in midbrain and thalamus. The ratio between the long and short form is similar in RT-PCR reaction. In human and rodent, the same two spliced forms are known to be coupled to G(i)-type heterotrimeric GTP binding protein, thereby opening an inwardly rectifying potassium channel, GIRK1. When the canine DRD2L and DRD2S were heterologously expressed in Xenopus oocytes, both forms activated GIRK1 potassium channels through coupling with G(i) protein. This activation was dose-dependent, demonstrating its ligand specificity. 相似文献
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178.
A case of chronic cerebral paragonimiasis westermani 总被引:1,自引:0,他引:1
We report a chronic cerebral paragonimiasis from a 41-year-old Korean man who complains a headache and weakness of left motor neuron components. Magnetic resonance images of the brain revealed conglomerates of multiple ring-like enhancements in temporo-occipital and frontal lobes of the right hemisphere. An intradermal test for paragonimiasis westermani was positive. The patient was born near an endemic area of paragonimiasis and used to eat boiled or grilled freshwater crayfish in his childhood. Nodules in the brain were resected through craniotomies. The eggs of P. westermani were identified pathologically and parasitologically in the calcified necrotic lesions. Examinations on sputum and fecal specimens for the eggs of P. westermani were shown to be negative and a chest radiograph was normal. It is presumed that the brain lesions were formed by P. westermani approximately 30 years ago. 相似文献
179.
180.
Kang BN Ha SG Ge XN Reza Hosseinkhani M Bahaie NS Greenberg Y Blumenthal MN Puri KD Rao SP Sriramarao P 《American journal of physiology. Lung cellular and molecular physiology》2012,302(11):L1179-L1191
Trafficking and recruitment of eosinophils during allergic airway inflammation is mediated by the phosphatidylinositol 3-kinase (PI3K) family of signaling molecules. The role played by the p110δ subunit of PI3K (PI3K p110δ) in regulating eosinophil trafficking and recruitment was investigated using a selective pharmacological inhibitor (IC87114). Treatment with the PI3K p110δ inhibitor significantly reduced murine bone marrow-derived eosinophil (BM-Eos) adhesion to VCAM-1 as well as ICAM-1 and inhibited activation-induced changes in cell morphology associated with reduced Mac-1 expression and aberrant cell surface localization/distribution of Mac-1 and α4. Infused BM-Eos demonstrated significantly decreased rolling and adhesion in inflamed cremaster muscle microvessels of mice treated with IC87114 compared with vehicle-treated mice. Furthermore, inhibition of PI3K p110δ significantly attenuated eotaxin-1-induced BM-Eos migration and prevented eotaxin-1-induced changes in the cytoskeleton and cell morphology. Knockdown of PI3K p110δ with siRNA in BM-Eos resulted in reduced rolling, adhesion, and migration, as well as inhibition of activation-induced changes in cell morphology, validating its role in regulating trafficking and migration. Finally, in a mouse model of cockroach antigen-induced allergic airway inflammation, oral administration of the PI3K p110δ inhibitor significantly inhibited airway eosinophil recruitment, resulting in attenuation of airway hyperresponsiveness in response to methacholine, reduced mucus secretion, and expression of proinflammatory molecules (found in inflammatory zone-1 and intelectin-1). Overall, these findings indicate the important role played by PI3K p110δ in mediating BM-Eos trafficking and migration by regulating adhesion molecule expression and localization/distribution as well as promoting changes in cell morphology that favor recruitment during inflammation. 相似文献