ABSTRACT
Wnt signaling has emerged as a major regulator of tissue development by governing the self-renewal and maintenance of stem cells in most tissue types. As a key upstream regulator of the Wnt pathway, the transmembrane E3 ligase ZNRF3 has recently been established to play a role in negative regulation of Wnt signaling by targeting Frizzled (FZD) receptor for ubiquitination and degradation. However, the upstream regulation of ZNRF3, in particular the turnover of ZNRF3, is still unclear. Here we report that ZNRF3 is accumulated in the presence of proteasome inhibitor treatment independent of its E3-ubiquitin ligase activity. Furthermore, the Cullin 1-specific SCF complex containing β-TRCP has been identified to directly interact with and ubiquitinate ZNRF3 thereby regulating its protein stability. Similar with the degradation of β-catenin by β-TRCP, ZNRF3 is ubiquitinated by β-TRCP in both CKI-phosphorylation- and degron-dependent manners. Thus, our findings not only identify a novel substrate for β-TRCP oncogenic regulation, but also highlight the dual regulation of Wnt signaling by β-TRCP in a context-dependent manner where β-TRCP negatively regulates Wnt signaling by targeting β-catenin, and positively regulates Wnt signaling by targeting ZNRF3.
Subject(s)
Humans , Cells, Cultured , Proteolysis , Ubiquitin-Protein Ligases , Metabolism , Ubiquitination , beta-Transducin Repeat-Containing Proteins , MetabolismABSTRACT
OBJECTIVE: To investigate the characteristics and regularity of ADR cases caused by leflunomide, and to provide reference for rational use of it. METHODS: Literatures about leflunomide-inducing ADR were retrieved from CNKI between 1994 and Apr. 2010. Those literatures were statistically analyzed in respect of patient’s age and gender, route of administration, dosage of drugs, onset time of ADR, organs and systems involved in ADR and its clinical manifestations, treatment and outcomes, etc. RESULTS: 37 pieces of literatures were obtained with standard cases of 45. The incidence of ADR cases in female(75.56%) was higher than in males (24.44%). 28 ADR cases were in 50～60 group. 39 patients were treated with leflunomide 10～30 mg once a day. After treatment, the most common gastrointestinal adverse events occurred in 1～15 d. Leflunomide-inducing ADR was digestive system reaction (75.56%) the most. Patients who took medicine less than 10 days with mild ADR need not to stop taking medicine when clinical symptoms reduced or disappeared after symptomatic treatment. Patients who took medicine more than 10 days with severe ADR need to stop taking medicine and receive symptomatic treatment. CONCLUSION: Clinical physicians should pay attention to rational use of leflunomide and ADR during treatment course to reduce the harm due to adverse events.
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OBJECTIVE:To study the effects of clozapine on blood glucose and insulin levels in schizophrenic patients. METHODS:This is a self-controlled study in which the levels of blood glucose and insulin in clozapine group(n=63) were compared before and after treatment,and which were compared with the levels in the control group(n=64).Insular cellular antibody(ICA) and insulin autoantibody(IAA) were detected in patients with high level of blood glucose.RESULTS:After treatment for 8 weeks,the blood glucose level was increased in clozapine group as compared with the same group before treatment and the control group,showing significant differences(P
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OBJECTIVE: To establish GC-MS method for the determination of the Menthol in inclusion complex of compound essential oil-? -cyclodextrin. METHODS: Menthol was determined with ion fragment peak ( M/Z=71) . The chromatographic column was DM-5 fused silica capillary column ( 0. 25mm? 30m) ; the internal standard was naphthol and the temperature programming was 80～ 180℃ . RESULTS: The calibration curves of Menthol were linear in the ranges of 1. 344～ 10. 752? g? mL-1( r=0. 999 8) and the average recovery was 97. 52% , RSD=1. 56% . CONCLUSION: The method is rapid, accurate and reproducible, and suitable for the quality control of the same kind of the preparation.
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OBJECTIVE:To evaluate the distribution and drugs resistance of pathogenic bacteria causing nosocomial infection over 2 years in our hospital.METHODS:A total of 4 653 strains of pathogens were analyzed statistically by retrospective study.RESULTS:Among 4 653 strains of pathogens,709 were fungi(15.2%),1 078 were Gram-positive cocci(23.2%)and 2 866 were Gram-negative bacilli(61.6%).Over the 2 years,the detection rates of extended spectrum ?-lactamase-producing Escherichia coli and Klebsiella spp.were 36.5% and 27.9%,respectively.The average resistance rate of Gram-positive cocci to penicillin,oxacillin,cefazolin,erythromycin,Co-trimoxazole and ciprofloxacin over the 2 years were 84.5%.The average resistance rate of Gram-negative bacilli to ampicillin was 96.0% and to cefotaxime,cefepime,gentamycin,Co-trimoxazole,ciprofloxacin and aztreonam were 52.7% in 2 years.CONCLUSION:Over the 2 years,Gram-negative bacilliin strains causing hospital nosocomial infections increased,Gram-positive cocci strains remain stable,but fungous infection showed a decline tendency.In view of the increasing drug resistance,rational use of antimicrobial agents should be stressed in the clinic.