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31.
Sivan Vadakkadath Meethal Miguel J Gallego Ryan J Haasl Stephen J Petras III Jean-Yves Sgro Craig S Atwood 《BMC evolutionary biology》2006,6(1):103-17
Background
The Caenorhabditis elegans genome is known to code for at least 1149 G protein-coupled receptors (GPCRs), but the GPCR(s) critical to the regulation of reproduction in this nematode are not yet known. This study examined whether GPCRs orthologous to human gonadotropin-releasing hormone receptor (GnRHR) exist in C. elegans. 相似文献32.
33.
Partitioning-defective protein 6 (Par-6) activates atypical protein kinase C (aPKC) by pseudosubstrate displacement 总被引:2,自引:0,他引:2
Atypical protein kinase C (aPKC) controls cell polarity by modulating substrate cortical localization. Aberrant aPKC activity disrupts polarity, yet the mechanisms that control aPKC remain poorly understood. We used a reconstituted system with purified components and a cultured cell cortical displacement assay to investigate aPKC regulation. We find that aPKC is autoinhibited by two domains within its NH(2)-terminal regulatory half, a pseudosubstrate motif that occupies the kinase active site, and a C1 domain that assists in this process. The Par complex member Par-6, previously thought to inhibit aPKC, is a potent activator of aPKC in our assays. Par-6 and aPKC interact via PB1 domain heterodimerization, and this interaction activates aPKC by displacing the pseudosubstrate, although full activity requires the Par-6 CRIB-PDZ domains. We propose that, along with its previously described roles in controlling aPKC localization, Par-6 allosterically activates aPKC to allow for high spatial and temporal control of substrate phosphorylation and polarization. 相似文献
34.
Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer's disease transgenic mice. 总被引:34,自引:0,他引:34
R A Cherny C S Atwood M E Xilinas D N Gray W D Jones C A McLean K J Barnham I Volitakis F W Fraser Y Kim X Huang L E Goldstein R D Moir J T Lim K Beyreuther H Zheng R E Tanzi C L Masters A I Bush 《Neuron》2001,30(3):665-676
Inhibition of neocortical beta-amyloid (Abeta) accumulation may be essential in an effective therapeutic intervention for Alzheimer's disease (AD). Cu and Zn are enriched in Abeta deposits in AD, which are solubilized by Cu/Zn-selective chelators in vitro. Here we report a 49% decrease in brain Abeta deposition (-375 microg/g wet weight, p = 0.0001) in a blinded study of APP2576 transgenic mice treated orally for 9 weeks with clioquinol, an antibiotic and bioavailable Cu/Zn chelator. This was accompanied by a modest increase in soluble Abeta (1.45% of total cerebral Abeta); APP, synaptophysin, and GFAP levels were unaffected. General health and body weight parameters were significantly more stable in the treated animals. These results support targeting the interactions of Cu and Zn with Abeta as a novel therapy for the prevention and treatment of AD. 相似文献
35.
Magnification, an increase in 18S + 28S ribosomal RNA genes, occurs in germ-line cells of rDNA-defecient Drosophila and resilts in a chromosomal change in rRNA gene number. Although differing hypotheses have been advanced, current evidence favors unequal sister chromatid exchange as the basis of this system of gene amplification. Genetic studies implicate repair activities in the process of magnification. 相似文献
36.
The rates of reaction of catechol cyclic phosphate in water and in acetonitrile-water demonstrate that imidazolium ion and metal ions (Na+, Mg2+, Zn2+) cause significant accelerations. These studies provide models for the potential role of cations in catalysis of reactions of phosphate anions by enzymes. In catalysis by Zn2+, we find that two to three imidazoles are required for coordination to Zn2+ for most effective catalysis. Enough water must be present to solvate imidazole and coordinate to Zn2+, indicating that a coordinated H2O is the nucleophile in Zn2+ catalysis. Product analysis also supports this conclusion. 相似文献
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39.
R J Castellani P L Harris L M Sayre J Fujii N Taniguchi M P Vitek H Founds C S Atwood G Perry M A Smith 《Free radical biology & medicine》2001,31(2):175-180
Advanced glycation end products are a diverse class of posttranslational modifications, stemming from reactive aldehyde reactions, that have been implicated in the pathogenesis of a number of degenerative diseases. Because advanced glycation end products are accelerated by, and result in formation of, oxygen-derived free radicals, they represent an important component of the oxidative stress hypothesis of Alzheimer disease (AD). In this study, we used in situ techniques to assess N(epsilon)-(Carboxymethyl)lysine (CML), the predominant advanced glycation end product that accumulates in vivo, along with its glycation-specific precursor hexitol-lysine, in patients with AD as well as in young and aged-matched control cases. Both CML and hexitol-lysine were increased in neurons, especially those containing intracellular neurofibrillary pathology in cases of AD. The increase in hexitol-lysine and CML in AD suggests that glycation is an early event in disease pathogenesis. In addition, because CML can result from either lipid peroxidation or advanced glycation, while hexitol-lysine is solely a product of glycation, this study, together with studies demonstrating the presence of 4-hydroxy-2-nonenal adducts and pentosidine, provides evidence of two distinct oxidative processes acting in concert in AD neuropathology. Our findings support the notion that aldehyde-mediated modifications, together with oxyradical-mediated modifications, are critical pathogenic factors in AD. 相似文献
40.
X. Zhu Y. Wang O. Ogawa H. G. Lee A. K. Raina H. Fujioka S. Shimohama C. S. Atwood R. B. Petersen G. Perry M. A. Smith 《Journal of neurochemistry》2002,81(Z1):76-76
The mechanisms underlying neuronal degeneration in Alzheimer's disease (AD) are very controversial and none more so than whether apoptosis plays a role. Although neurons in AD face a wide assortment of apoptogenic stimuli, the temporal dichotomy between the acuteness of apoptosis vs. the chronicity of AD suggests that apoptosis should be extremely rare in AD. In this regard, survival factor(s) must be involved. In this study, we investigated Bcl‐w, a pro‐survival member of the Bcl‐2 family. Although expressed at low levels in brains of control cases, Bcl‐w is significantly up‐regulated in AD as shown by both immunocytochemistry and immunoblot analysis. Astonishingly, increased Bcl‐w was found to be associated with neurofibrillary pathologies in AD, which was further demonstrated by an EM study. Since neuronal death in AD is thought to be triggered by increased production of amyloid‐β (Aβ), it was interesting to find that exposure of human M17 neuroblastoma cells to Aβ1–42 (1 nm ?10 μm ) dramatically up‐regulates Bcl‐w protein levels. Such increases may be a protective response that attenuates apoptotic processes. Consistent with this, transfected M17 cells overexpressing Bcl‐w were protected from both STS‐induced and Aβ‐induced apoptosis compared to vector‐transfected controls. Notably, both tau phosphorylation and p38 is inhibited in Bcl‐w transfected cells which may contribute to the neuroprotective role of Bcl‐w. Taken together, these set of in vitro and in vivo results suggest that Bcl‐w plays an important protective role in neurons in the AD brain. 相似文献