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961.
Screening of large numbers of Acinetobacter spp. from activated sludge systems with Pyrolysis Mass Spectrometry (PyMS) showed that many did not cluster tightly with the currently described genomic species which have been obtained mainly from clinical sources. Selected isolates were then genotypically fingerprinted using their 16S-23S rDNA spacer region, and again the data revealed considerable differences in the genomic fingerprints of many of these activated sludge isolates to the predominantly clinical genomic species. In fact, few could be identified from them. The possibility that the current speciation within this genus is not adequate to encompass all these environmental isolates is addressed in relation to the methods used to study the population dynamics of Acinetobacter in activated sludge. 相似文献
962.
Interleukin 23 (IL-23) is a new member of the IL-12 family that plays a critical role in promoting the proliferation of memory T helper 1 cells. The heterodimerized IL-23 receptor is composed of a shared IL-12 receptor beta 1 (IL-12Rβ1) and an IL-12Rβ2-related molecule called IL-23R. The standard form of IL-23R is encoded by at least 12 exons. Here, we demonstrate that at least six spliced isoforms of IL-23R (IL-23R1 to 6) can be generated through alternative splicing. The splicing strategies for the IL-23R gene are complicated and most often result in the deletion of exon 7 and/or exon 10. Translation prediction revealed that these spliced variants result in either premature termination to give rise to a diverse form of receptor ectodomain, or a frameshift to generate various lengths of the IL-23R endodomain. Differential expressions of IL-23R spliced variants are observed in natural killer and CD3+CD4+ T cells. The expressions of these spliced variants are also prevalently and complicatedly regulated in tumor cell lines. Interestingly, only IL-23R2 and/or IL-23R4 variants are predominantly detected in certain human lung carcinomas, but not in their resected normal margin tissues. Thus, our results indicate that the regulation of alternative splicing on the IL-23R gene is complicated, and the preferential expression of certain IL-23R spliced variants may be a contributive factor to the pathogenesis of certain cancers. 相似文献
963.
964.
Recent studies from multiple laboratories, including our own, provided fresh insights into the contributory roles for GTP-binding proteins (G-proteins) in glucose-stimulated insulin secretion (GSIS) from the islet β cell. However, the precise mechanisms underlying the activation of this class of signaling proteins by insulin secretagogues remain only partially understood. We recently proposed that nm23/nucleoside diphosphate kinase (NDPK) catalyzes an alternate, non-receptor-dependent activation of islet endogenous G-proteins. In further support of this proposal, we report, herein, that overexpression of wild type (WT) nm23-H1 mutant in INS cells markedly potentiated GSIS. However, an inactive mutant of nm23-H1(H118F), which is deficient in histidine kinase and NDPK activities, was considerably less effective in potentiating GSIS from these cells, suggesting that both of these activities may be relevant for the potentiating effects of nm23-H1. Potential significance of these findings in relation to contributory roles for nm23/NDPK-like enzymes in the stimulus-secretion coupling of GSIS is discussed. 相似文献
965.
Nm23/NDP kinases in hepatocellular carcinoma 总被引:3,自引:0,他引:3
One of the most aggressive cancers is hepatocellular carcinoma, which is associated with a very poor patient outcome due to a high recurrence rate and metastatic spread. NM23, the first metastasis suppressor gene to be identified, has been widely studied in human cancers. However, conflicting results have been obtained depending on the tumor type and the evaluation protocol. The current knowledge of NM23 as a diagnostic and/or prognostic marker in hepatocellular carcinoma is reviewed herein. Most studies demonstrate an inverse association between the expression of NM23-H1 and the metastatic potential, which is not observed with the closely related NM23-H2 isoform. Transfection of metastatic hepatoma cells with NM23 reduced their metastatic potential, as for other tumor cell lines. The demonstration of a causative role of NM23 in metastatic dissemination in a mouse model of hepatocarcinoma suggests that hepatocarcinoma-derived cells could be good models for the analysis of the molecular mechanisms involved in NM23 action. 相似文献
966.
Garzia L Roma C Tata N Pagnozzi D Pucci P Zollo M 《Journal of bioenergetics and biomembranes》2006,38(3-4):205-213
Cancer is a multi-step process, one of the latest events correspond to metastasis formation and dissemination, to date the major cause of deaths. The h-prune-nm23-H1 protein complex and its activation of PDE-cAMP activity have been shown to correlate with breast cancer progression and metastasis formation. Here, we describe the protein complex formation and its involvement in cell migration. By gene expression studies and protein-protein pull-down analyses coupled to mass spectrometry we have identified new genes and pathways along which the h-prune-nm23-H1 complex exerts its function. We review here h-prune binding to the glycogen synthase kinase (GSK-3β) and identify a new h-prune protein partner, Gelsolin, an ATP severing protein acting in focal adhesions, in a MDA-435 breast cancer cellular model. The results presented here underline the importance of this protein complex leading to new translational studies involved into the inhibition of cell migration, thus enhancing the potential of using this knowledge to direct inhibition of metastases formation in humans. 相似文献
967.
Bouvard D Millon-Fremillon A Dupe-Manet S Block MR Albiges-Rizo C 《European journal of cell biology》2006,85(3-4):275-282
Cell adhesion to either the extracellular matrix (ECM) or to neighboring cells is of critical importance during both physiological and pathological situations. Integrins are a large family of cell adhesion receptors composed of two non-covalently linked alpha and beta subunits. They have a well-identified dual function of mediating both firm adhesion and signaling. The short cytoplasmic domain of integrin can interact with cytoplasmic proteins that are either shared by several different integrins or specific for one type of integrin. Integrin cytoplasmic domain-associated protein-1 (ICAP-1) is a small cytoplasmic protein that specifically interacts with the beta1 integrin subunit. In this review we will discuss recent findings on ICAP-1, not only at the structural and functional level, but also its possible interconnection in other signaling pathways such as those that control cell proliferation. 相似文献
968.
Kang Y Vossler RA Diaz-Martinez LA Winter NS Clarke DJ Walters KJ 《Journal of molecular biology》2006,356(4):1027-1035
The ubiquitin-proteasome pathway is essential throughout the life cycle of a cell. This system employs an astounding number of proteins to ubiquitylate and to deliver protein substrates to the proteasome for their degradation. At the heart of this process is the large and growing family of ubiquitin receptor proteins. Within this family is an intensely studied group that contains both ubiquitin-like (UBL) and ubiquitin-associated (UBA) domains: Rad23, Ddi1 and Dsk2. Although UBL/UBA family members are reported to regulate the degradation of other proteins, their individual roles in ubiquitin-mediated protein degradation has proven difficult to resolve due to their overlapping functional roles and interaction with each other and other ubiquitin family members. Here, we use a combination of NMR spectroscopy and molecular biology to reveal that Rad23 and Ddi1 interact with each other by using UBL/UBA domain interactions in a manner that does not preclude their interaction with ubiquitin. We demonstrate that UBL/UBA proteins can bind a common tetraubiquitin molecule and thereby provide strong evidence for a model in which chains adopt an opened structure to bind multiple receptor proteins. Altogether our results suggest a mechanism through which UBL/UBA proteins could protect chains from premature de-ubiquitylation and unnecessary elongation during their transit to the proteasome. 相似文献
969.
Luginbühl B Kanyo Z Jones RM Fletterick RJ Prusiner SB Cohen FE Williamson RA Burton DR Plückthun A 《Journal of molecular biology》2006,363(1):75-97
Bovine spongiform encephalopathy (BSE) is a fatal neurodegenerative prion disease affecting cattle that is transmissible to humans, manifesting as a variant of Creutzfeldt-Jakob disease (vCJD) likely following the consumption of meat contaminated with BSE prions. High-affinity antibodies are a prerequisite for the development of simple, highly sensitive and non-invasive diagnostic tests that are able to detect even small amounts of the disease-associated PrP conformer (PrP(Sc)). We describe here the affinity maturation of a single-chain Fv antibody fragment with a binding affinity of 1 pM to a peptide derived from the unstructured region of bovine PrP (BoPrP (90-105)). This is the tightest peptide-binding antibody reported to date and may find useful application in diagnostics, especially when PrP(Sc) is pretreated by denaturation and/or proteolysis for peptide-like presentation. Several rounds of directed evolution and off-rate selection with ribosome display were performed using an antibody library generated from a single PrP binder with error-prone PCR and DNA-shuffling. As the correct determinations of affinities in this range are not straightforward, competition biosensor techniques and KinExA methods were both applied and compared. Structural interpretation of the affinity improvement was performed based on the crystal structure of the original prion binder in complex with the BoPrP (95-104) peptide by modeling the corresponding mutations. 相似文献
970.
Golan G Zharkov DO Grollman AP Dodson ML McCullough AK Lloyd RS Shoham G 《Journal of molecular biology》2006,362(2):241-258
The base excision repair (BER) pathway for ultraviolet light (UV)-induced cyclobutane pyrimidine dimers is initiated by DNA glycosylases that also possess abasic (AP) site lyase activity. The prototypical enzyme known to catalyze these reactions is the T4 pyrimidine dimer glycosylase (T4-Pdg). The fundamental chemical reactions and the critical amino acids that lead to both glycosyl and phosphodiester bond scission are known. Catalysis proceeds via a protonated imine covalent intermediate between the alpha-amino group of the N-terminal threonine residue and the C1' of the deoxyribose sugar of the 5' pyrimidine at the dimer site. This covalent complex can be trapped as an irreversible, reduced cross-linked DNA-protein complex by incubation with a strong reducing agent. This active site trapping reaction is equally efficient on DNA substrates containing pyrimidine dimers or AP sites. Herein, we report the co-crystal structure of T4-Pdg as a reduced covalent complex with an AP site-containing duplex oligodeoxynucleotide. This high-resolution structure reveals essential precatalytic and catalytic features, including flipping of the nucleotide opposite the AP site, a sharp kink (approximately 66 degrees ) in the DNA at the dimer site and the covalent bond linking the enzyme to the DNA. Superposition of this structure with a previously published co-crystal structure of a catalytically incompetent mutant of T4-Pdg with cyclobutane dimer-containing DNA reveals new insights into the structural requirements and the mechanisms involved in DNA bending, nucleotide flipping and catalytic reaction. 相似文献