{"database":"biostudies-literature","file_versions":[],"scores":{"citationCount":0,"reanalysisCount":0,"viewCount":65,"searchCount":0},"additional":{"submitter":["Hong X"],"funding":["NIA NIH HHS","NCI NIH HHS","NIH HHS"],"pagination":["8855-8869"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC5062998"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["44(18)"],"pubmed_abstract":["SOX9 encodes a transcription factor that governs cell fate specification throughout development and tissue homeostasis. Elevated SOX9 is implicated in the genesis and progression of human tumors by increasing cell proliferation and epithelial-mesenchymal transition. We found that in response to UV irradiation or genotoxic chemotherapeutics, SOX9 is actively degraded in various cancer types and in normal epithelial cells, through a pathway independent of p53, ATM, ATR and DNA-PK. SOX9 is phosphorylated by GSK3β, facilitating the binding of SOX9 to the F-box protein FBW7α, an E3 ligase that functions in the DNA damage response pathway. The binding of FBW7α to the SOX9 K2 domain at T236-T240 targets SOX9 for subsequent ubiquitination and proteasomal destruction. Exogenous overexpression of SOX9 after genotoxic stress increases cell survival. Our findings reveal a novel regulatory mechanism for SOX9 stability and uncover a unique function of SOX9 in the cellular response to DNA damage. This new mechanism underlying a FBW7-SOX9 axis in cancer could have implications in therapy resistance."],"journal":["Nucleic acids research"],"pubmed_title":["SOX9 is targeted for proteasomal degradation by the E3 ligase FBW7 in response to DNA damage."],"pmcid":["PMC5062998"],"funding_grant_id":["R01 CA166575","R01 CA195612","S10 OD016400","R01 CA190578","K01 AG041218","R01 CA190858"],"pubmed_authors":["Liu L","Feng X","Shah JJ","Liu W","Sabaawy HE","Shen Z","Hong X","Morgan KM","Pine SR","Song R","Zheng XF","Inuzuka H","Bunting SF","Tsang CK"],"view_count":["65"],"additional_accession":[]},"is_claimable":false,"name":"SOX9 is targeted for proteasomal degradation by the E3 ligase FBW7 in response to DNA damage.","description":"SOX9 encodes a transcription factor that governs cell fate specification throughout development and tissue homeostasis. Elevated SOX9 is implicated in the genesis and progression of human tumors by increasing cell proliferation and epithelial-mesenchymal transition. We found that in response to UV irradiation or genotoxic chemotherapeutics, SOX9 is actively degraded in various cancer types and in normal epithelial cells, through a pathway independent of p53, ATM, ATR and DNA-PK. SOX9 is phosphorylated by GSK3β, facilitating the binding of SOX9 to the F-box protein FBW7α, an E3 ligase that functions in the DNA damage response pathway. The binding of FBW7α to the SOX9 K2 domain at T236-T240 targets SOX9 for subsequent ubiquitination and proteasomal destruction. Exogenous overexpression of SOX9 after genotoxic stress increases cell survival. Our findings reveal a novel regulatory mechanism for SOX9 stability and uncover a unique function of SOX9 in the cellular response to DNA damage. This new mechanism underlying a FBW7-SOX9 axis in cancer could have implications in therapy resistance.","dates":{"release":"2016-01-01T00:00:00Z","publication":"2016 Oct","modification":"2024-11-08T19:27:23.206Z","creation":"2019-03-27T02:26:35Z"},"accession":"S-EPMC5062998","cross_references":{"pubmed":["27566146"],"doi":["10.1093/nar/gkw748"]}}