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81.
Citri A Harari D Shohat G Ramakrishnan P Gan J Lavi S Eisenstein M Kimchi A Wallach D Pietrokovski S Yarden Y 《The Journal of biological chemistry》2006,281(20):14361-14369
Hsp90 is a highly abundant chaperone whose clientele includes hundreds of cellular proteins, many of which are central players in key signal transduction pathways and the majority of which are protein kinases. In light of the variety of Hsp90 clientele, the mechanism of selectivity of the chaperone toward its client proteins is a major open question. Focusing on human kinases, we have demonstrated that the chaperone recognizes a common surface in the amino-terminal lobe of kinases from diverse families, including two newly identified clients, NFkappaB-inducing kinase and death-associated protein kinase, and the oncoprotein HER2/ErbB-2. Surface electrostatics determine the interaction with the Hsp90 chaperone complex such that introduction of a negative charge within this region disrupts recognition. Compiling information on the Hsp90 dependence of 105 protein kinases, including 16 kinases whose relationship to Hsp90 is first examined in this study, reveals that surface features, rather than a contiguous amino acid sequence, define the capacity of the Hsp90 chaperone machine to recognize client kinases. Analyzing Hsp90 regulation of two major signaling cascades, the mitogen-activated protein kinase and phosphatidylinositol 3-kinase, leads us to propose that the selectivity of the chaperone to specific kinases is functional, namely that Hsp90 controls kinases that function as hubs integrating multiple inputs. These lessons bear significance to pharmacological attempts to target the chaperone in human pathologies, such as cancer. 相似文献
82.
Iwai M Kanno H Senba I Nakaoka H Moritani T Horiuchi M 《Biochemical and biophysical research communications》2011,(1):403-126
The effect of the PPARγ agonistic action of an AT1 receptor blocker, irbesartan, on adipose tissue dysfunction was explored using atherosclerotic model mice. Adult male apolipoprotein E-deficient (ApoEKO) mice at 9 weeks of age were treated with a high-cholesterol diet (HCD) with or without irbesartan at a dose of 50 mg/kg/day for 4 weeks. The weight of epididymal and retroperitoneal adipose tissue was decreased by irbesartan without changing food intake or body weight. Treatment with irbesartan increased the expression of PPARγ in white adipose tissue and the DNA-binding activity of PPARγ in nuclear extract prepared from adipose tissue. The expression of adiponectin, leptin and insulin receptor was also increased by irbesartan. These results suggest that irbesartan induced activation of PPARγ and improved adipose tissue dysfunction including insulin resistance. 相似文献
83.
84.
Nan R Farabella I Schumacher FF Miller A Gor J Martin AC Jones DT Lengyel I Perkins SJ 《Journal of molecular biology》2011,408(4):714-735
The Tyr402His polymorphism of complement factor H (FH) with 20 short complement regulator (SCR) domains is associated with age-related macular degeneration (AMD). How FH contributes to disease pathology is not clear. Both FH and high concentrations of zinc are found in drusen deposits, the key feature of AMD. Heterozygous FH is inhibited by zinc, which causes FH to aggregate. Here, zinc binding to homozygous FH was studied. By analytical ultracentrifugation, large amounts of oligomers were observed with both the native Tyr402 and the AMD-risk His402 homozygous allotypes of FH and both the recombinant SCR-6/8 allotypes with Tyr/His402. X-ray scattering also showed that both FH and SCR-6/8 allotypes strongly aggregated at > 10 μM zinc. The SCR-1/5 and SCR-16/20 fragments were less likely to bind zinc. These observations were supported by bioinformatics predictions. Starting from known zinc binding sites in crystal structures, we predicted 202 putative partial surface zinc binding sites in FH, most of which were in SCR-6. Metal site prediction web servers also suggested that SCR-6 and other domains bind zinc. Predicted SCR-6/8 dimer structures showed that zinc binding sites could be formed at the protein-protein interface that would lead to daisy-chained oligomers. It was concluded that zinc binds weakly to FH at multiple surface locations, most probably within the functionally important SCR-6/8 domains, and this explains why zinc inhibits FH activity. Given the high pathophysiological levels of bioavailable zinc present in subretinal deposits, we discuss how zinc binding to FH may contribute to deposit formation and inflammation associated with AMD. 相似文献
85.
David Y Ternette N Edelmann MJ Ziv T Gayer B Sertchook R Dadon Y Kessler BM Navon A 《The Journal of biological chemistry》2011,286(51):44104-44115
Ubiquitin-conjugating enzymes (E2s) have a dominant role in determining which of the seven lysine residues of ubiquitin is used for polyubiquitination. Here we show that tethering of a substrate to an E2 enzyme in the absence of an E3 ubiquitin ligase is sufficient to promote its ubiquitination, whereas the type of the ubiquitin conjugates and the identity of the target lysine on the substrate are promiscuous. In contrast, when an E3 enzyme is introduced, a clear decision between mono- and polyubiquitination is made, and the conjugation type as well as the identity of the target lysine residue on the substrate becomes highly specific. These features of the E3 can be further regulated by auxiliary factors as exemplified by MDMX (Murine Double Minute X). In fact, we show that this interactor reconfigures MDM2-dependent ubiquitination of p53. Based on several model systems, we propose that although interaction with an E2 is sufficient to promote substrate ubiquitination the E3 molds the reaction into a specific, physiologically relevant protein modification. 相似文献
86.
Dunaliella bardawil, a beta-carotene-accumulating alga was treated by the bleaching herbicide norflurazon to select sub-species rich with a mixture of 9-cis and all-trans stereoisomers of phytoene and phytofluene. The present study determines the bioavailability of phytoene and phytofluene with their stereoisomers in rats fed on a diet supplemented with Dunaliella phytoene-rich spray dried powder. Three groups of female weanling rats, eight animals each, were fed AIN diets for two weeks. The control consumed the diet as is. The experimental group was supplemented with 50 g Dunaliella powder to give phytoene/phytofluene at a level of 1 g/kg diet, and the placebo was provided with the oxidized algae free of carotenoids at the same amount. Weight gain and tissues weight of rats fed on the control diet, or on the experimental diets were statistically same. Tissue analyses were carried out by liquid chromatography at the end of two weeks feeding for vitamin A, carotenoids, phytoene and phytofluene and theirs stereoisomers. Liver analyses revealed high hepatic storage of phytoene in the experimental group. Analysis of the other tissues, adrenal, brain, heart, kidney, lung, and spleen detected small amounts of phytoene in the adrenal, kidney and spleen and in the plasma. High-pressure liquid chromatography for stereoisomeric composition was performed to all phytoene-containing tissues. The original algal diet content of 9-cis-to-all-trans ratio of 1:1 was maintained in the plasma and adrenal while in the liver, spleen and kidney the ratio was reduced to 1:3. The preferential accumulation of all-trans phytoene over 9-cis phytoene in the liver, spleen and kidney may be interpreted as indicating stronger antioxidative effect of 9-cis phytoene over the all-trans isomer or alternatively, in vivo streoisomerization of 9-cis phytoene to the all-trans structure. 相似文献
87.
Peter A. McCue Tiziana DeAngelis Renato Baserga Ami Fujii Hallgeir Rui Michael J. Mastrangelo Takami Sato 《Pigment cell & melanoma research》2014,27(2):297-308
We investigated the importance of the insulin‐like growth factor‐1 receptor (IGF‐1R) in hepatic metastases of uveal melanoma. The expression pattern of IGF‐1R in archival tissue samples of hepatic metastasis from 24 patients was analyzed by immunohistochemistry. All the samples of hepatic metastases stained positive for IGF‐1R. To investigate the biological role of IGF‐1R on the growth of metastatic uveal melanoma, a long‐term cell line obtained from a hepatic metastasis (TJU‐UM001) was evaluated. TJU‐UM001 expressed cell surface IGF‐1R (>90%) and proliferated in response to exogenous and endogenous insulin‐like growth factor‐1 (IGF‐1). Correlatively, anti‐IGF‐1R antibody completely blocked IGF‐1‐induced growth of TJU‐UM001 cells. IGF‐1 preferentially induced phosphorylation of Akt (S473) in quiescent TJU‐UM001 cells, and this was blocked by anti‐IGF‐1R antibody. This study suggests that autocrine and paracrine mechanisms underlie IGF‐1‐induced growth of metastatic uveal melanoma and underscore the potential benefit of IGF‐1 or IGF‐1R antagonism in treatment for metastatic uveal melanoma. 相似文献
88.
Ken-Ichi Hanaki Fumio Ike Ayako Kajita Wataru Yasuno Misato Yanagiba Motoki Goto Kouji Sakai Yasushi Ami Shigeru Kyuwa 《PloS one》2014,9(5)
A one-step SYBR Green I real-time RT-PCR assay was developed for the detection and quantification of a broad range of murine noroviruses (MNVs). The primer design was based on the multiple sequence alignments of 101 sequences of the open reading frame (ORF)1−ORF2 junction of MNV. The broad reactivity and quantitative capacity of the assay were validated using 7 MNV plasmids. The assay was completed within 1 h, and the reliable detection limit was 10 copies of MNV plasmid or 0.063 median tissue culture infective doses per milliliter of RAW264 cell culture-propagated viruses. The diagnostic performance of the assay was evaluated using 158 mouse fecal samples, 91 of which were confirmed to be positive. The melting curve analysis demonstrated the diversity of MNV in the samples. This is the first report of a broadly reactive one-step SYBR Green I real-time RT-PCR assay for detecting of MNVs. The rapid and sensitive performance of this assay makes it a powerful tool for diagnostic applications. 相似文献
89.
Ami Cohen Timothy W. Whitfield Max Kreifeldt Pascale Koebel Brigitte L. Kieffer Candice Contet Olivier George George F. Koob 《PloS one》2014,9(5)
Dynorphins, endogenous opioid peptides that arise from the precursor protein prodynorphin (Pdyn), are hypothesized to be involved in the regulation of mood states and the neuroplasticity associated with addiction. The current study tested the hypothesis that dynorphin in the nucleus accumbens (NAcc) mediates such effects. More specifically, we examined whether knockdown of Pdyn within the NAcc in rats would alter the expression of depressive-like and anxiety-like behavior, as well as cocaine locomotor sensitization. Wistar rats were injected with adeno-associated viral (AAV) vectors encoding either a Pdyn-specific short hairpin RNA (AAV-shPdyn) or a scrambled shRNA (AAV-shScr) as control. Four weeks later, rats were tested for anxiety-like behavior in the elevated plus maze test and depressive-like behavior in the forced swim test (FST). Finally, rats received one daily injection of saline or cocaine (20 mg/kg, i.p.), followed by assessment of locomotion for 4 consecutive days. Following 3 days of abstinence, the rats completed 2 additional daily cocaine/saline locomotor trials. Pdyn knockdown in the NAcc led to a significant reduction in depressive-like behavior in the FST, but had no effect on anxiety-like behavior in the elevated plus maze. Pdyn knockdown did not alter baseline locomotor behavior, the locomotor response to acute cocaine, or the initial sensitization of the locomotor response to cocaine over the first 4 cocaine treatment days. However, following 3 days abstinence the locomotor response to the cocaine challenge returned to their original levels in the AAV-shPdyn rats while remaining heightened in the AAV-shScr rats. These results suggest that dynorphin in a very specific area of the nucleus accumbens contributes to depressive-like states and may be involved in neuroadaptations in the NAcc that contribute to the development of cocaine addiction as a persistent and lasting condition. 相似文献
90.
Ido Wolf Shiri Shahmoon Michal Ben Ami Yael Levy-Shraga Kineret Mazor-Aronovitch Orit Pinhas-Hamiel Yonatan Yeshayahu Rina Hemi Hannah Kanety Tami Rubinek Dalit Modan-Moses 《PloS one》2014,9(9)