A portrayal of E3 ubiquitin ligases and deubiquitylases in cancer

Abstract

E3 ubiquitin ligases and deubiquitylating enzymes (DUBs) are the key components of ubiquitin proteasome system which plays a critical role in cellular protein homeostasis. Any shortcoming in their biological roles can lead to various diseases including cancer. The dynamic interplay between ubiquitylation and deubiquitylation determines the level and activity of several proteins including p53, which is crucial for cellular stress response and tumor suppression pathways. In this review, we describe the different types of E3 ubiquitin ligases including those targeting tumor suppressor p53, SCF ligases and RING type ligases and accentuate on biological functions of few important E3 ligases in the cellular regulatory networks. Tumor suppressor p53 level is tightly regulated by multiple E3 ligases including Mdm2, COP1, Pirh2, etc. SCF ubiquitin ligase complexes are key regulators of cell cycle and signal transduction. BRCA1 and VHL RING type ligases function as tumor suppressors and play an important role in DNA repair and hypoxia response respectively. Further, we discuss the biological consequences of deregulation of the E3 ligases and the implications for cancer development. We also describe deubiquitylases which reverse the process of ubiquitylation and regulate diverse cellular pathways including metabolism, cell cycle control and chromatin remodelling. As the E3 ubiquitin ligases and DUBs work in a substrate specific manner, an improved understanding of them can lead to better therapeutics for cancer.Cancer is best characterized at molecular level either by gainof-function of oncoproteins and/or loss-of-function of tumor suppressor proteins. The turnover and the biological activity of several oncoproteins and tumor suppressors is governed by the ubiquitin proteasome system (UPS). The UPS comprises two distinct steps: the covalent attachment of multiple ubiquitin molecules to the protein substrate and degradation of the polyubiquitylated protein by the 26S proteasome complex. 1 A ubiquitin molecule consists of a highly conserved 76-amino-acid polypeptide that is conjugated through an isopeptide linkage to other proteins. Key structural features of ubiquitin include its b-grasp fold, its C-terminal tail and seven lysine residues through which polyubiquitin chains are linked. The most important lysine residues of ubiquitin are K48 and K63. K48-linked polyubiquitylation targets the protein for proteasomal degradation while linear ubiquitin chains, monoubiquitylation and K63-linked polyubiquitylation play a role in signalling.The first step of UPS is cascaded by at least three enzymes: the ubiquitin-activating enzyme E1, ubiquitin-conjugating enzyme E2 and ubiquitin ligase E3. A role for E1 in cancer has not been described, and only a few reports have correlated E2 to tumorigenesis. 2 In contrast, cumulative evidence suggests alterations in the activity of many E3 ligases in the etiology of cancer development. 3,4 Because E3 ligases are the recognition element of the system, thus by providing the substrate specificit...

UBE2S is associated with malignant characteristics of breast cancer cells

“…There are additional E3 ligases whose mutation or dysregulation is associated with cancer progression. For example, germline mutations of the BRCA1 gene are predictors for the risk of ovarian and breast cancers [16,17]. Von Hippel-Lindau (VHL) E3 ligase was originally identified as a tumor suppressor, and somatic mutations of the VHL gene are related to the development of clear cell renal carcinoma [18].…”

Rescue of embryonic stem cells from cellular transformation by proteomic stabilization of mutant p53 and conversion into WT conformation

“…This notion is further supported by a recent publication by Trinidad et al (17) that showed that p53-dependent gene expression requires folding of WT p53 by the CCT complex. Interestingly, many of the ubiquitin-like binders were shown to regulate p53 (18). Specifically, USP7 was shown to stabilize p53 by deubiquitylating it, even in the presence of high levels of Mdm2 (19).…”

Expression of ubiquitin specific peptidase and ATG7 genes in U87 glioma cells upon glutamine deprivation

“…It is released from degraded proteins by disassembly of the polyubiquitin chains, which is mediated by ubiquitin-specific proteases, members of the ubiquitin-specific processing family of proteases for deubiquitination of proteins [7][8][9]. E3 ubiquitin ligases and deubiquitylases play an important role in cancer [7,10,11].…”