Ubiquitin in Cell-Cycle Regulation and Dysregulation in Cancer

Uncontrolled cell proliferation and genomic instability are common features of cancer and can arise from, respectively, the loss of cell-cycle control and defective checkpoints. Ubiquitin-mediated proteolysis, ultimately executed by ubiquitin-ligating enzymes (E3s), plays a key part in cell-cycle regulation and is dominated by two multisubunit E3s, the anaphase-promoting complex (or cyclosome) (APC/C) and SKP1-cullin-1-F-box (SCF) complex. We highlight the role of APC/C and the SCF bound to F-box proteins, FBXW7, SKP2, and beta-TrCP, in regulating the abundance of select fundamental proteins, primarily during the cell cycle, that are associated with human cancer. The clinical success of the first proteasome inhibitor, bortezomib, in treating multiple myeloma and mantle-cell lymphoma set the precedent for viewing the ubiquitin-proteasome system as a druggable target for cancer. Given that there are more E3s than kinases, selective, small-molecule E3 inhibitors have the potential of opening up another dimension in the therapeutic armamentarium for the treatment of cancer.