In higher eukaryotic cells, the p53 protein is degraded by the ubiquitin-26S proteasome system mediated by Mdm2 or the human papilloma virus E6 protein. Here we show that COP9 signalosome (CSN)-specific phosphorylation targets human p53 to ubiquitin-26S proteasome-dependent degradation. As visualized by electron microscopy, p53 binds with high affinity to the native CSN complex. p53 interacts via its N-terminus with CSN subunit 5/Jab1 as shown by far-western and pull-down assays. The CSN-specific phosphorylation sites were mapped to the core domain of p53 including Thr155. A phosphorylated peptide, Deltap53(145-164), specifically inhibits CSN-mediated phosphorylation and p53 degradation. Curcumin, a CSN kinase inhibitor, blocks E6-dependent p53 degradation in reticulocyte lysates. Mutation of Thr155 to valine is sufficient to stabilize p53 against E6-dependent degradation in reticulocyte lysates and to reduce binding to Mdm2. The p53T155V mutant accumulates in both HeLa and HL 60 cells and exhibits a mutant (PAb 240+) conformation. It induces the cyclin-dependent inhibitor p21. In HeLa and MCF-7 cells, inhibition of CSN kinase by curcumin or Deltap53(145-164) results in accumulation of endogenous p53.
Background Hip fracture patients are frail and have a high mortality. We investigated whether the introduction of fast track care reduced the 30-day mortality after hip fractures. Methods Fast track hip fracture care was established at our institution in October 2013. Data from the Norwegian Hip Fracture Register and electronic hospital records were merged for 2230 hip fracture patients operated in our department from January 2012 through December 2015. 1090 of these patients were operated before (conventional treatment group) and 1140 patients were operated after the introduction of fast track care (fast track group). Data were analysed by univariate analysis and binary logistic regression. Results Mortality did not differ significantly between the conventional treatment group and the fast track group at 30 days (7.9% vs. 6.5%), 90 days (13.5% vs. 12.5%) and one year (22.8% vs. 22.8%). Median admission time and time to surgery were significantly shorter in the fast track group than in the conventional treatment group (1.1 h vs. 3.9 h and 23.6 h vs. 25.7 h, both p < 0.0001). The 30-day reoperation rate was significantly lower in the fast track group compared to the conventional treatment group (odds ratio = 0.35 (95% CI: 0.15–0.84), p = 0.019). A composite 30-day outcome (reoperation, surgical site infection and/or death) was significantly less frequent in the fast track group (8.1%) than in the conventional treatment group (10.7%) in unadjusted analysis ( p = 0.006), but not after adjusting for age, gender, cognitive impairment and ASA score (odds ratio = 0.85 (95% CI: 0.63–1.16), p = 0.31, 8.0% missing). Reoperations within 1 year, surgical site infections, 30-day readmissions and length of hospital stay did not differ significantly between the conventional treatment group and the fast track group. Conclusions Fast track hip fracture care is safe. However, we observed no statistically significant change in 30-day, 90-day or 1-year mortality after the introduction of fast track hip fracture care. Trial registration The study was registered retrospectively at ClinicalTrials.gov (Protocol Record 284907 ) 6 December 2016.
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