The role of cullin proteins in gastric cancer

The cullin proteins are a family of scaffolding proteins that associate with RING proteins and ubiquitin E3 ligases and mediate substrate-receptor bindings. Thus, cullin proteins regulate the specificity of ubiquitin targeting in the regulation of proteins involved in various cellular processes, including proliferation, differentiation, and apoptosis. There are seven cullin proteins that have been identified in eukaryotes: CUL1, CUL2, CUL3, CUL4A, CUL4B, CUL5, and CUL7/p53-associated parkin-like cytoplasmic protein. All of these proteins contain a conserved cullin homology domain that binds to RING box proteins. Cullin-RING ubiquitin ligase complexes are activated upon post-translational modification by neural precursor cell-expressed, developmentally downregulated protein 8. The aberrant expression of several cullin proteins has been implicated in many cancers though the significance in gastric cancer has been less well investigated. This review provides the first systematic discussion of the associations between all members of the cullin protein family and gastric cancer. Functional and regulatory mechanisms of cullin proteins in gastric carcinoma progression are also summarized along with a discussion concerning future research areas. Accumulating evidence suggests a critical role of cullin proteins in tumorigenesis, and a better understanding of the function of these individual cullin proteins and their targets will help identify potential biomarkers and therapeutic targets.