The ubiquitin-proteasome pathway and its role in cancer.
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.
Mani
Aparna
A
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, 3800 Reservoir Rd NW, Washington, DC 20007-2197, USA.
Gelmann
Edward P
EP
D019313:BRCA1 Protein / Q000235:genetics; D002292:Carcinoma, Renal Cell / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000502:physiology; D015179:Colorectal Neoplasms / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27; D005260:Female; D005909:Glioblastoma / Q000378:metabolism; D006801:Humans; D007680:Kidney Neoplasms / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000502:physiology; D025801:Ubiquitin / Q000378:metabolism*; D002583:Uterine Cervical Neoplasms / Q000378:metabolism
D019313:BRCA1 Protein; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; D050760:Cyclin-Dependent Kinase Inhibitor p27; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D046988:Proteasome Endopeptidase Complex