Targeting the ubiquitin-proteasome system for cancer therapy.
The ubiquitin-proteasome system plays a critical role in controlling the level, activity and location of various cellular proteins. Significant progress has been made in investigating the molecular mechanisms of ubiquitination, particularly in understanding the structure of the ubiquitination machinery and identifying ubiquitin protein ligases, the primary specificity-determining enzymes. Therefore, it is now possible to target specific molecules involved in ubiquitination and proteasomal degradation to regulate many cellular processes such as signal transduction, proliferation and apoptosis. In particular, alterations in ubiquitination are observed in most, if not all, cancer cells. This is manifested by destabilization of tumor suppressors, such as p53, and overexpression of oncogenes such as c-Myc and c-Jun. In addition to the development and clinical validation of proteasome inhibitor, bortezomib, in myeloma therapy, recent studies have demonstrated that it is possible to develop inhibitors for specific ubiquitination and deubiquitination enzymes. With the help of structural studies, rational design and chemical synthesis, it is conceivable that we will be able to use 'druggable' inhibitors of the ubiquitin system to evaluate their effects in animal tumor models in the not-so-distant future.
Yang
Yili
Y
Cancer and Developmental Biology Laboratory, National Cancer Institute at Frederick, National Institutes of Health, Frederick, MD 21702, USA. yangyili@ncifcrf.gov
Kitagaki
Jirouta
J
Wang
Honghe
H
Hou
De-Xing
DX
Perantoni
Alan O
AO
D000074749:Deubiquitinating Enzyme CYLD; D019398:Genes, BRCA1; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011480:Protease Inhibitors / Q000627:therapeutic use*; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D061988:Proteasome Inhibitors; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics; D025801:Ubiquitin / Q000378:metabolism*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism
D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D044786:S-Phase Kinase-Associated Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD; D046988:Proteasome Endopeptidase Complex; C497446:VHL protein, human