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941.
Kwang-jin Cho Jin-Hee Park Andrew M. Piggott Angela A. Salim Alemaheyu A. Gorfe Robert G. Parton Robert J. Capon Ernest Lacey John F. Hancock 《The Journal of biological chemistry》2012,287(52):43573-43584
Oncogenic mutant Ras is frequently expressed in human cancers, but no anti-Ras drugs have been developed. Since membrane association is essential for Ras biological activity, we developed a high content assay for inhibitors of Ras plasma membrane localization. We discovered that staurosporine and analogs potently inhibit Ras plasma membrane binding by blocking endosomal recycling of phosphatidylserine, resulting in redistribution of phosphatidylserine from plasma membrane to endomembrane. Staurosporines are more active against K-Ras than H-Ras. K-Ras is displaced to endosomes and undergoes proteasomal-independent degradation, whereas H-Ras redistributes to the Golgi and is not degraded. K-Ras nanoclustering on the plasma membrane is also inhibited. Ras mislocalization does not correlate with protein kinase C inhibition or induction of apoptosis. Staurosporines selectively abrogate K-Ras signaling and proliferation of K-Ras-transformed cells. These results identify staurosporines as novel inhibitors of phosphatidylserine trafficking, yield new insights into the role of phosphatidylserine and electrostatics in Ras plasma membrane targeting, and validate a new target for anti-Ras therapeutics. 相似文献
942.
Elena López Villar Duojiao Wu William C. Cho Luis Madero Xiangdong Wang 《Journal of cellular and molecular medicine》2014,18(7):1239-1246
There are important breakthroughs in the treatment of paediatric acute lymphoblastic leukaemia (ALL) since 1950, by which the prognosis of the child majority suffered from ALL has been improved. However, there are urgent needs to have disease‐specific biomarkers to monitor the therapeutic efficacy and predict the patient prognosis. The present study overviewed proteomics‐based research on paediatric ALL to discuss important advances to combat cancer cells and search novel and real protein biomarkers of resistance or sensitivity to drugs which target the signalling networks. We highlighted the importance and significance of a proper phospho‐quantitative design and strategy for paediatric ALL between relapse and remission, when human body fluids from cerebrospinal, peripheral blood, or bone‐marrow were applied. The present article also assessed the schedule for the analysis of body fluids from patients at different states, importance of proteomics‐based tools to discover ALL‐specific and sensitive biomarkers, to stimulate paediatric ALL research via proteomics to ‘build’ the reference map of the signalling networks from leukemic cells at relapse, and to monitor significant clinical therapies for ALL‐relapse. 相似文献
943.
Jong A Wu CH Gonzales-Gomez I Kwon-Chung KJ Chang YC Tseng HK Cho WL Huang SH 《The Journal of biological chemistry》2012,287(19):15298-15306
Cryptococcus neoformans is a pathogenic yeast that can invade the brain and cause meningoencephalitis. Our previous in vitro studies suggested that the interaction between C. neoformans hyaluronic acid and human brain endothelial CD44 could be the initial step of brain invasion. In this report, we used a CD44 knock-out (KO or CD44(-/-)) mouse model to explore the importance of CD44 in C. neoformans brain invasion. Our results showed that C. neoformans-infected CD44 KO mice survived longer than the infected wild-type mice. Consistent with our in vitro results, the brain and cerebrospinal fluid fungal burden was reduced in CD44-deficient mice. Histopathological studies showed smaller and fewer cystic lesions in the brains of CD44 KO mice. Interestingly, the cystic lesions contained C. neoformans cells embedded within their polysaccharide capsule and were surrounded by host glial cells. We also found that a secondary hyaluronic acid receptor, RHAMM (receptor of hyaluronan-mediated motility), was present in the CD44 KO mice. Importantly, our studies demonstrated an in vivo blocking effect of simvastatin. These results suggest that the CD44 and RHAMM receptors function on membrane lipid rafts during invasion and that simvastatin may have a potential therapeutic role in C. neoformans infections of the brain. 相似文献
944.
Cho JN Ryu JY Jeong YM Park J Song JJ Amasino RM Noh B Noh YS 《Developmental cell》2012,22(4):736-748
For optimal survival, various environmental and endogenous factors should be monitored to determine the appropriate timing for seed germination. Light is a major environmental factor affecting seed germination, which is perceived by phytochromes. The light-dependent activation of phytochrome B (PHYB) modulates abscisic acid and gibberellic acid signaling and metabolism. Thus far, several negative regulators of seed germination that act when PHYB is inactive have been reported. However, neither positive regulators of seed germination downstream of PHYB nor a direct mechanism for regulation of the hormone levels has been elucidated. Here, we show that the histone arginine demethylases, JMJ20 and JMJ22, act redundantly as positive regulators of seed germination. When PHYB is inactive, JMJ20/JMJ22 are directly repressed by the zinc-finger protein SOMNUS. However, upon PHYB activation, JMJ20/JMJ22 are derepressed, resulting in increased gibberellic acid levels through the removal of repressive histone arginine methylations at GA3ox1/GA3ox2, which in turn promotes seed germination. 相似文献
945.
Purpose
To evaluate the effects of prostatic anatomical factors on male lower urinary tract symptoms (LUTS) and the peak flow rate (Qmax) in patients with small prostate volume (PV).Materials and Methods
Records were obtained from a prospectively maintained database of first-visit men with LUTS. Patients whose total PV (TPV) was greater than 30 mL were excluded; 444 patients were enrolled in the study. The TPV, transitional zone volume (TZV), transitional zone index (TZI), intravesical prostatic protrusion (IPP), and prostatic urethral angle (PUA) were measured by transrectal ultrasonography. LUTS were evaluated using the International Prostate Symptom Score (IPSS) and the Overactive Bladder Symptom Score (OABSS) questionnaires. Uroflowmetric measurements were also made.Results
PUA (r = 0.269, P<0.001), TZV (r = 0.160, P<0.001), and TZI (r = 0.109, P = 0.022) significantly correlated with the IPSS. Qmax (r = −0.334, P<0.001) and OABSS (r = 0.211, P<0.001) correlated only with PUA. In a multivariate regression analysis, PUA and age were independently associated with IPSS, OABSS, and Qmax. For IPSS of 20 or greater, the area under the ROC curve (AUC) of PUA was 0.667 and the cut-off value was 43.7°. When Qmax was 10 mL/s or less, the AUC of PUA was 0.664 and the cut-off value was 43.5°.Conclusions
PUA has a significant association with symptom severity and Qmax among prostatic anatomical factors analyzed in men with LUTS and small PV. PUA should be considered as an important clinical factor in male LUTS management. Furthermore, the impact of PUA on response to medical treatment and disease progression needs to be investigated. 相似文献946.
Kathryn A. Radigan Luisa Morales-Nebreda Saul Soberanes Trevor Nicholson Recep Nigdelioglu Takugo Cho Monica Chi Robert B. Hamanaka Alexander V. Misharin Harris Perlman G. R. Scott Budinger G?khan M. Mutlu 《PloS one》2014,9(9)
Rationale
During the recent H1N1 outbreak, obese patients had worsened lung injury and increased mortality. We used a murine model of influenza A pneumonia to test the hypothesis that leptin receptor deficiency might explain the enhanced mortality in obese patients.Methods
We infected wild-type, obese mice globally deficient in the leptin receptor (db/db) and non-obese mice with tissue specific deletion of the leptin receptor in the lung epithelium (SPC-Cre/LepRfl/fl) or macrophages and alveolar type II cells (LysM-Cre/Leprfl/fl) with influenza A virus (A/WSN/33 [H1N1]) (500 and 1500 pfu/mouse) and measured mortality, viral clearance and several markers of lung injury severity.Results
The clearance of influenza A virus from the lungs of mice was impaired in obese mice globally deficient in the leptin receptor (db/db) compared to normal weight wild-type mice. In contrast, non-obese, SP-C-Cre+/+/LepRfl/fl and LysM-Cre+/+/LepRfl/fl had improved viral clearance after influenza A infection. In obese mice, mortality was increased compared with wild-type mice, while the SP-C-Cre+/+/LepRfl/fl and LysM-Cre+/+/LepRfl /fl mice exhibited improved survival.Conclusions
Global loss of the leptin receptor results in reduced viral clearance and worse outcomes following influenza A infection. These findings are not the result of the loss of leptin signaling in lung epithelial cells or macrophages. Our results suggest that factors associated with obesity or with leptin signaling in non-myeloid populations such as natural killer and T cells may be associated with worsened outcomes following influenza A infection. 相似文献947.
Su Jin Kim Jinhong Cho Eun Joo Song Soo Jin Kim Ho Min Kim Kyung Eun Lee Se Won Suh Eunice EunKyeong Kim 《The Journal of biological chemistry》2014,289(18):12264-12274
Valosin-containing protein (VCP), also known as p97, is an AAA+ ATPase that plays an essential role in a broad array of cellular processes including the endoplasmic reticulum-associated degradation (ERAD) pathway. Recently, ERAD-specific deubiquitinating enzymes have been reported to be physically associated with VCP, although the exact mechanism is not yet clear. Among these enzymes is ovarian tumor domain-containing protein 1 (OTU1). Here, we report the structural basis for interaction between VCP and OTU1. The crystal structure of the ubiquitin regulatory X-like (UBXL) domain of OTU1 (UBXLOTU1) complexed to the N-terminal domain of VCP (NVCP) at 1.8-Å resolution reveals that UBXLOTU1 adopts a ubiquitin-like fold and binds at the interface of two subdomains of NVCP using the 39GYPP42 loop of UBXLOTU1 with the two prolines in cis- and trans-configurations, respectively. A mutagenesis study shows that this loop is not only critical for the interaction with VCP but also for its role in the ERAD pathway. Negative staining EM shows that one molecule of OTU1 binds to one VCP hexamer, and isothermal titration calorimetry suggests that the two proteins bind with a KD of 0.71 μm. Analytical size exclusion chromatography and isothermal titration calorimetry demonstrates that OTU1 can bind VCP in both the presence and absence of a heterodimer formed by ubiquitin fusion degradation protein 1 and nuclear localization protein 4. 相似文献
948.
Kim N Yoo JC Han JY Hwang EM Kim YS Jeong EY Sun CH Yi GS Roh GS Kim HJ Kang SS Cho GJ Park JY Choi WS 《Journal of cellular physiology》2012,227(3):1157-1167
Clusterin (CLU), a glycoprotein, is involved in apoptosis, producing two alternatively spliced isoforms in various cell types. The pro-apoptotic CLU appears to be a nuclear isoform (nuclear clusterin; nCLU), and the secretory CLU (sCLU) is thought to be anti-apoptotic. The detailed molecular mechanism of nCLU as a pro-apoptotic molecule has not yet been clear. In the current study, overexpressed nCLU induced apoptosis in human kidney cells. Biochemical studies revealed that nCLU sequestered Bcl-XL via a putative BH3 motif in the C-terminal coiled coil (CC2) domain, releasing Bax, and promoted apoptosis accompanied by activation of caspase-3 and cytochrome c release. These results suggest a novel mechanism of apoptosis mediated by nCLU as a pro-apoptotic molecule. 相似文献
949.
Status of metacercarial infections of Paragonimus westermani was observed in freshwater crabs, which were purchased at 3 markets in its peak season of 1990. All of 85 crabs were Eriocheir japonicus. No other species of Eriocheir were found. When crushed muscle and viscera was examined individually, the infection rate was 11.8%; and mean number of metacercariae was 2.1 per infected crab. Unless adequately cooked, freshwater crabs are still potential sources of human paragonimiasis. 相似文献
950.
The alpha subunit of type II Ca2+/calmodulin-dependent protein kinase is highly conserved in Drosophila 总被引:2,自引:0,他引:2
A monoclonal antibody against rat brain type II Ca2+/calmodulin-dependent protein kinase (CaM kinase) precipitates three proteins from Drosophila heads with apparent molecular weights similar to those of the subunits of the rat brain kinase. Fly heads also contain a CaM kinase activity that becomes partially independent of Ca2+ after autophosphorylation, as does the rat brain kinase. We have isolated a Drosophila cDNA encoding an amino acid sequence that is 77% identical to the sequence of the rat alpha subunit. All known autophosphorylation sites are conserved, including the site that controls Ca(2+)-independent activity. The gene encoding the cDNA is located between 102E and F on the fourth chromosome. The protein product of this gene is expressed at much higher levels in the fly head than in the body. Thus, both the amino acid sequence and the tissue specificity of the mammalian kinase are highly conserved in Drosophila. 相似文献