Background
The deubiquitylating enzymes (DUBs) regulate ubiquitin dependent signaling pathways. The activities of the DUBs include the generation of free ubiquitin from precursor molecules, the recycling of ubiquitin following substrate degradation to maintain cellular ubiquitin homeostasis and the removal of ubiquitin or ubiquitin-like proteins (UBL) modifications through chain editing to rescue proteins from proteasomal degradation or to influence cell signalling events (Komander et al., 2009). There are two main classes of DUB, cysteine proteases and metalloproteases. Ubiquitin specific processing protease 7 (USP-7) is a member of the cysteine protease enzyme family and cloning of the gene in humans was first described by Everett et al. (1997). Overexpression of p53 and USP7 stabilizes p53 through the removal of ubiquitin moieties from polyubiquitylated p53 (Kon et al., 2010). Inhibition of USP7 expression results in the accumulation and stabilisation of p53 protein. However, USP7 has been shown to stabilise mdm2 a ubiquitin ligase that promotes the degradation of p53 (Holowaty and Frappier. 2004; Krishna and Grishin. 2004). Thus USP7 appears to play multiple roles in regulating the p53/mdm2 pathway and maintaining steady-state levels of p53 in the cell. Due to the role USP7 has been shown to play in the regulation of p53 its importance as a therapeutic target for treating hematopoietic tumours has been highlighted (Cheon and Baek. 2006).
References
Cheon KW, Baek KH (2006) HAUSP as a therapeutic target for hematopoietic tumors (review). Int J Oncol 28, 1209-15.
Everett RD, Meredith M, Orr A, Cross A, Kathoria M, Parkinson J (1997) A novel ubiquitin-specific protease is dynamically associated with the PML nuclear domain and binds to a herpesvirus regulatory protein. EMBO J 16, 1519-30.
Holowaty MN, Frappier L (2004) HAUSP/USP7 as an Epstein-Barr virus target. Biochem Soc Trans 32, 731-2.
Komander D, Clague MJ, Urbe S (2009) Breaking the chains: structure and function of the deubiquitinases. Nat Rev Mol Cell Biol 10, 550-63.
Kon N, Kobayashi Y, Li M, Brooks CL, Ludwig T, Gu W (2010) Inactivation of HAUSP in vivo modulates p53 function. Oncogene 29, 1270-9.
Krishna SS, Grishin NV (2004) The finger domain of the human deubiquitinating enzyme HAUSP is a zinc ribbon. Cell Cycle 3, 1046-9.