From the Division of Hematology/Oncology, Department of Pediatrics and Department of Pathology and Laboratory Medicine; Jonsson Comprehensive Cancer Center; and David Geffen School of Medicine, Molecular Biology Institute and California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA
Author's disclosure of potential conflicts of interest are found at the end of this article.
Address reprint requests to Kathleen M. Sakamoto, MD, PhD, Pediatrics, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, Los Angeles, CA. 90095-1752; e-mail: kms{at}ucla.edu
Overview: The ubiquitin proteasome pathway is the major mechanism by which proteins are degraded or modified for specific cellular functions. Ubiquitin is a small 9-kd protein that attaches to the lysine residues of target proteins through a series of enzymatic reactions involving a ubiquitin-activating enzyme E1, a ubiquitin-conjugating enzyme E2, and an E3 ubiquitin ligase. Substrate specificity is conferred by the E3 ligase. Substrates of E3 ligases have been found to be mutated or aberrantly expressed in human cancer. These substrates include tumor suppressors, such as p53. E3 ligases themselves can also be mutated or dysregulated (e.g., von Hippel-Lindau protein). Substrates of E3 RING ligases, such as Cbl, target oncogenic proteins (e.g., epidermal growth factor receptor). Small molecules, such as cis-imidazolines, have been developed to target E3 ubiquitin ligase MDM2 to stabilize p53 in tumor cells. More recently, alternative approaches to recruit cancer-causing proteins to E3 ubiquitin ligases have been developed. For example, chimeric molecules have been engineered to induce ubiquitination and degradation of specific targets in cancer cells. Ubiquitin-like modifications, such as sumoylation and neddylation, are also critical for protein function in normal and cancer cells. Specific examples of potential targets of the ubiquitin and ubiquitin-like modifier pathways for cancer therapy will be reviewed.
