Cullin Family Proteins and Tumorigenesis: Genetic Association and Molecular Mechanisms

Abstract

Cullin family proteins function as scaffolds to form numerous E3 ubiquitin ligases with RING proteins, adaptor proteins and substrate recognition receptors. These E3 ligases further recognize numerous substrates to participate in a variety of cellular processes, such as DNA damage and repair, cell death and cell cycle progression. Clinically, cullin-associated E3 ligases have been identified to involve numerous human diseases, especially with regard to multiple cancer types. Over the past few years, our understanding of cullin proteins and their functions in genome stability and tumorigenesis has expanded enormously. Herein, this review briefly provides current perspectives on cullin protein functions, and mainly summarizes and discusses molecular mechanisms of cullin proteins in tumorigenesis.

Structure‐Guided Design of Peptides as Tools to Probe the Protein–Protein Interaction between Cullin‐2 and Elongin BC Substrate Adaptor in Cullin RING E3 Ubiquitin Ligases

“…CRLs, of which over 230 are estimated in human cells, are responsible for approximately 20 % of the ubiquitin‐dependent protein turnover in cells, being implicated in a number of cellular processes across different organisms . The significant roles of CRLs in several biological processes and human diseases has rapidly emerged, in particular in cancer, where the genes encoding for E3 ligase subunits and their native substrates are often found as oncogenes or tumor suppressors . Currently, much focus is directed toward targeting E3 CRLs with small molecules, such as inhibitors, to block the ligase activity; molecular glues, to redirect E3 CRL activity toward neo‐substrates; and bivalent PROTACs, to induce targeted protein degradation .…”

CRL4BDCAF11 E3 ligase targets p21 for degradation to control cell cycle progression in human osteosarcoma cells

“…Dysregulation of these Cullin members has been broadly reported to contribute to tumourigenesis through diverse mechanisms such as their involvement in DNA damage and repair, cell cycle progression, and the ubiquitination of oncoproteins or tumour suppressors 12 . Our previous work revealed that the CUL4B gene was overexpressed in the osteosarcoma cell line Saos-2 26 .…”

“…The CRLs recognize different substrates and affect a wide variety of cellular processes, including tumourigenesis 12 . Of particular interest in our studies are the CRL4 E3 ligases, which are formed by Cullin 4 (CUL4), RING-box protein 1 (RBX1), the adaptor protein-damaged DNA binding protein 1 (DDB1), and the DDB1 and CUL4-associated factors (DCAFs) 12, 14, 15 .…”

Regulation of Mammalian DNA Replication via the Ubiquitin-Proteasome System

“…Family members include eight cullin proteins (cullins 1, 2, 3, 4A, 4B, 5, 7, and 9 (also known as PARC or p53-associated parkin-like cytoplasmic protein)) and a cullin-like protein ANAPC2 or APC2. The general description of the structure and function of CRLs has been described in several excellent reviews (Chen et al 2015; Lydeard et al 2013; Sarikas et al 2011; Duda et al 2011; Hua and Vierstra 2011; Lipkowitz and Weissman 2011; Deshaies and Joazeiro 2009; Hotton and Callis 2008). The SCF ( S KP1- C ullin1- F -Box protein; also known as CRL1, Fig.…”