The ubiquitin-proteasome pathway and its role in cancer.
ABSTRACT Critical cellular processes are regulated, in part, by maintaining the appropriate intracellular levels of proteins. Whereas de novo protein synthesis is a comparatively slow process, proteins are rapidly degraded at a rate compatible with the control of cell cycle transitions and cell death induction. A major pathway for protein degradation is initiated by the addition of multiple 76-amino acid ubiquitin monomers via a three-step process of ubiquitin activation and substrate recognition. Polyubiquitination targets proteins for recognition and processing by the 26S proteasome, a cylindrical organelle that recognizes ubiquitinated proteins, degrades the proteins, and recycles ubiquitin. The critical roles played by ubiquitin-mediated protein turnover in cell cycle regulation makes this process a target for oncogenic mutations. Oncogenes of several common malignancies, for example colon and renal cell cancer, code for ubiquitin ligase components. Cervical oncogenesis by human papillomavirus is also mediated by alteration of ubiquitin ligase pathways. Protein degradation pathways are also targets for cancer therapy, as shown by the successful introduction of bortezomib, an inhibitor of the 26S proteasome. Further work in this area holds great promise toward our understanding and treatment of a wide range of cancers.
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ABSTRACT: Osteosarcoma is the most common bone tumor in children, adolescents, and young adults. In contrast to other childhood malignancies, no biomarkers have been consistently identified as predictors of outcome. This study was conducted to assess the microRNAs(miRs) expression signatures in pre-treatment osteosarcoma specimens and correlate with outcome to identify biomarkers for disease relapse. A 42-miRs signature whose expression levels were associated with overall and relapse-free survival waas identified. There were 8 common miRs between the two sets of survival-associated miRs. Bioinformatic analyses of these survival-associated miRs suggested that they might regulate genes involved in ubiquitin proteasome system, TGFb, IGF, PTEN/AKT/mTOR, MAPK, PDGFR/RAF/MEK/ERK, and ErbB/HER pathways. The cohort consisted of 27 patients of 70% Mexican-American ethnicity. High-throughput RT-qPCR approach was used to generate quantitative expression of 754 miRs in the human genome. We examined tumor recurrence status, survival time and their association with miR expression levels by Cox proportional hazard regression analysis. TargetScan was used to predict miR/genes interactions, and functional analyses using KEGG, BioCarta, Gene Ontology were applied to these potential targets to predict deregulated pathways. Our findings suggested that these miRs might be potentially useful as prognostic biomarkers and therapeutic targets in pediatric osteosarcoma.Oncoscience. 01/2014; 1(9):599-608.
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ABSTRACT: Silk fibroin (SF) is a protein with bulky hydrophobic domains and can be easily purified as sericin-free silk-based biomaterial. Silk fibroin modified chitosan nanoparticle (SF-CSNP), a biocompatible material, has been widely used as a potential drug delivery system. Our current investigation studied the bio-effects of the SF-CSNP uptake by liver cells. In this experiment, the characterizations of SF-CSNPs were measured by particle size analysis and protein assay. The average size of the SF-CSNP was 311.9 ± 10.7 nm, and the average zeta potential was +13.33 ± 0.3 mV. The SF coating on the SF-CSNP was 6.27 ± 0.17 μg/mL. Moreover, using proteomic approaches, several proteins involved in the ubiquitin proteasome pathway were identified by analysis of differential protein expressions of HepG2 cell uptake the SF-CSNP. Our experimental results have demonstrated that the SF-CSNP may be involved in liver cancer cell survival and proliferation.International Journal of Molecular Sciences 01/2014; 16(1):1657-76. · 2.46 Impact Factor
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ABSTRACT: Polyethylenimines (PEIs) are among the most efficient polycationic non-viral transfectants. PEI architecture and size not only modulate transfection efficiency, but also cytotoxicity. However, the underlying mechanisms of PEI-induced multifaceted cell damage and death are largely unknown. Here, we demonstrate that the central mechanisms of PEI architecture- and size-dependent perturbations of integrated cellular metabolomics involve destabilisation of plasma membrane and mitochondrial membranes with consequences on mitochondrial oxidative phosphorylation (OXPHOS), glycolytic flux and redox homeostasis that ultimately modulate cell death. In comparison to linear PEI, the branched architectures induced greater plasma membrane destabilisation and were more detrimental to glycolytic activity and OXPHOS capacity as well as being a more potent inhibitor of the cytochrome c oxidase. Accordingly, the branched architectures caused a greater lactate dehydrogenase (LDH) and ATP depletion, activated AMP kinase (AMPK) and disturbed redox homeostasis through diminished availability of nicotinamide adenine dinucleotide phosphate (NADPH), reduced antioxidant capacity of glutathione (GSH) and increased burden of reactive oxygen species (ROS). The differences in metabolic and redox imprints were further reflected in the transfection performance of the polycations, but co-treatment with the GSH precursor N-acetyl-cysteine (NAC) counteracted redox dysregulation and increased the number of viable transfected cells. Integrated biomembrane integrity and metabolomic analysis provides a rapid approach for mechanistic understanding of multifactorial polycation-mediated cytotoxicity, and could form the basis for combinatorial throughput platforms for improved design and selection of safer polymeric vectors. Copyright © 2014. Published by Elsevier B.V.Biochimica et Biophysica Acta (BBA) - Bioenergetics 12/2014; · 4.83 Impact Factor