The Role and Regulation of Cyclin G2 in Human Ovarian Cancer Cells
MetadataShow full item record
Epithelial Ovarian Cancer (EOC) is the leading cause of cancer related death associated with gynecological malignancies. Survival is greatly impeded by poor screening methods, non-specific symptoms, and limited knowledge of the cellular targets that contribute to disease. Cell division is under direct regulation of the cyclin family. Typical cyclins will accumulate periodically to activate cyclin-dependent kinases (CDKs) leading to the unidirectional flow of the cell cycle, whereas the unconventional G-type cyclins (cyclin G1, G2, and I) act to oppose cell cycle progression. Indeed, dysregulation of the cycle cell is an important molecular mechanism that is frequently altered in cancers, including EOC. Interestingly, recent evidence has suggested that the loss of cyclin G2 is associated with cancer progression and poor survival. In this study, we have investigated the role and regulation of cyclin G2 in EOC cells. We found that cyclin G2 overexpression decreases the overall tumor burden by reducing proliferation, migration, and invasion. Interestingly, these anti-tumorigenic effects are mediated, at least in part, by enhancement the epithelial phenotype via attenuation of β-catenin signaling. Cyclin G2 promotes the degradation of β-catenin and directs its sub-cellular localization to the membrane, possibly through up-regulation of E-cadherin. In addition, we have previously shown that cyclin G2 is highly unstable, and degraded very quickly by the ubiquitin-proteasome pathway. This study also suggests the calpain-mediated proteolysis is a major factor that contributes to the degradation of cyclin G2. This process is dependent on the presence of the cyclin G2 C-terminal PEST motif, as well as epidermal growth factor signalling. Together, these data suggest that the loss of cyclin G2 in human malignancies, possibly through growth factor signaling and multiple downstream degradation processes, may contribute to the increased tumorgenicity of ovarian cancer cells.