{"database":"biostudies-literature","file_versions":[],"scores":{"citationCount":0,"reanalysisCount":0,"viewCount":44,"searchCount":0},"additional":{"submitter":["Chen X"],"funding":["NIDCR NIH HHS","NCI NIH HHS"],"pagination":["1535-45"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC4158693"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["21(10)"],"pubmed_abstract":["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."],"journal":["Cell death and differentiation"],"pubmed_title":["Fbxo45-mediated degradation of the tumor-suppressor Par-4 regulates cancer cell survival."],"pmcid":["PMC4158693"],"funding_grant_id":["R01 DE119249","R37 CA076584","R01 CA140806","R01 CA136905"],"pubmed_authors":["Pagano M","Chung F","Rangnekar VM","Basrur V","Elenitoba-Johnson KS","Chen X","Sahasrabuddhe AA","Lim MS","Szankasi P"],"view_count":["44"],"additional_accession":[]},"is_claimable":false,"name":"Fbxo45-mediated degradation of the tumor-suppressor Par-4 regulates cancer cell survival.","description":"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.","dates":{"release":"2014-01-01T00:00:00Z","publication":"2014 Oct","modification":"2021-03-06T08:39:46Z","creation":"2019-03-27T01:35:25Z"},"accession":"S-EPMC4158693","cross_references":{"pubmed":["24992930"],"doi":["10.1038/cdd.2014.92"]}}