Deubiquitinating enzymes as novel anticancer targets.
Tagging proteins with mono- or poly-ubiquitin is now recognized as a multifaceted and universal means of regulating cell growth and physiology. It does so by controlling the cellular lifetime of nearly all eukaryotic proteins and the cellular localization of many critical proteins. Enzymes of the ubiquitin pathway add (ligases) or remove (deubiquitinases [DUBs]) ubiquitin tags to or from their target proteins in a selective fashion. Similarly to the kinases and their corresponding phosphatases, ubiquitin ligases and DUBs have become actively studied molecular oncology targets for drug discovery. Approximately 79 functional DUBs exist in the human proteome, suggesting that selective intervention is a reasonable therapeutic objective, with the goal of downregulating or ablating oncogene products or, alternatively, upregulating or sparing tumor suppressors. In the following review, this fascinating class of regulatory enzymes will be described, and specific examples of DUBs that are viable targets for anticancer therapy will be considered.
Nicholson
Benjamin
B
Progenra, Inc., 271A Great Valley Parkway, Malvern, PA 19355, USA. nicholson@progenra.com
Marblestone
Jeffrey G
JG
Butt
Tauseef R
TR
Mattern
Michael R
MR
D000970:Antineoplastic Agents / Q000494:pharmacology*; D016503:Drug Delivery Systems; D006801:Humans; D000075687:NEDD8 Protein; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D025841:Small Ubiquitin-Related Modifier Proteins / Q000187:drug effects; D025801:Ubiquitin / Q000187:drug effects* / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000187:drug effects; D014452:Ubiquitins / Q000187:drug effects
D000970:Antineoplastic Agents; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D025841:Small Ubiquitin-Related Modifier Proteins; C459591:USP20 protein, human; D025801:Ubiquitin; D014452:Ubiquitins; D043222:Ubiquitin Thiolesterase; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease