| First Author | Chen X | Year | 2014 |
| Journal | Cell Death Differ | Volume | 21 |
| Issue | 10 | Pages | 1535-45 |
| PubMed ID | 24992930 | Mgi Jnum | J:258152 |
| Mgi Id | MGI:6141672 | Doi | 10.1038/cdd.2014.92 |
| Citation | Chen X, et al. (2014) Fbxo45-mediated degradation of the tumor-suppressor Par-4 regulates cancer cell survival. Cell Death Differ 21(10):1535-45 |
| abstractText | Prostate apoptosis response protein 4 (Par-4) also known as PRKC apoptosis WT1 regulator is a tumor suppressor that selectively induces apoptosis in cancer cells. However, its post-translational regulation by ubiquitin-mediated proteolysis and the cellular machinery that is responsible for its proteasomal degradation are unknown. Using immunopurification and an unbiased mass spectrometry-based approach, we show that Par-4 interacts with the SPRY-domain containing E3 ubiquitin ligase Fbxo45 through a short consensus sequence motif. Fbxo45 interacts with Par-4 in the cytoplasm and mediates its ubiquitylation and proteasomal degradation. Fbxo45 silencing results in stabilization of Par-4 with increased apoptosis. Importantly, a Par-4 mutant that is unable to bind Fbxo45 is stabilized and further enhances staurosporine-induced apoptosis. Co-expression of Fbxo45 with Par-4 protects cancer cells against Par-4-induced apoptosis. Our studies reveal that Fbxo45 is the substrate-receptor subunit of a functional E3 ligase for Par-4 that has a critical role in cancer cell survival. |
