Role of ubiquitin ligases and the proteasome in oncogenesis: novel targets for anticancer therapies.
The ubiquitin proteasome system (UPS) regulates the ubiquitination, and thus degradation and turnover, of many proteins vital to cellular regulation and function. The UPS comprises a sequential series of enzymatic processes using four key enzyme families: E1 (ubiquitin-activating enzymes), E2 (ubiquitin-carrier proteins), E3 (ubiquitin-protein ligases), and E4 (ubiquitin chain assembly factors). Because the UPS is a crucial regulator of the cell cycle, and abnormal cell-cycle control can lead to oncogenesis, aberrancies within the UPS pathway can result in a malignant cellular phenotype and thus has become an attractive target for novel anticancer agents. This article will provide an overall review of the mechanics of the UPS, describe aberrancies leading to cancer, and give an overview of current drug therapies selectively targeting the UPS.
University of Colorado School of Medicine, Aurora, CO, USA.lindsey.micel@childrenscolorado.org
Lindsey N
LN
Micel
John J
JJ
Tentler
Peter G
PG
Smith
Gail S
GS
Eckhardt
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002471:Cell Transformation, Neoplastic; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000502:physiology; D004268:DNA-Binding Proteins / Q000502:physiology; D006801:Humans; D008297:Male; D009154:Mutation; D009856:Oncogene Proteins, Viral / Q000502:physiology; D011471:Prostatic Neoplasms / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000502:physiology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D044764:Ubiquitin-Activating Enzymes / Q000502:physiology*; D044763:Ubiquitin-Conjugating Enzymes / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; C052603:E6 protein, Human papillomavirus type 18; D009856:Oncogene Proteins, Viral; D016159:Tumor Suppressor Protein p53; C046288:ubiquitin carrier proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D044763:Ubiquitin-Conjugating Enzymes; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex; D044764:Ubiquitin-Activating Enzymes