title: Tumor-suppressor role for the SPOP ubiquitin ligase in signal-dependent proteolysis of the oncogenic co-activator SRC-3/AIB1.
abstract: Steroid receptor co-activator-3 (SRC-3/AIB1) is an oncogene that is amplified and overexpressed in many human cancers. However, the molecular mechanisms that regulate 'activated SRC-3 oncoprotein' turnover during tumorigenesis remain to be elucidated. Here, we report that speckle-type POZ protein (SPOP), a cullin 3 (CUL3)-based ubiquitin ligase, is responsible for SRC-3 ubiquitination and proteolysis. SPOP interacts directly with an SRC-3 phospho-degron in a phosphorylation-dependent manner. Casein kinase Iɛ phosphorylates the S102 in this degron and promotes SPOP-dependent turnover of SRC-3. Short hairpin RNA knockdown and overexpression experiments substantiated that the SPOP/CUL3/Rbx1 ubiquitin ligase complex promotes SRC-3 turnover. A systematic analysis of the SPOP genomic locus revealed that a high percentage of genomic loss or loss of heterozygosity occurs at this locus in breast cancers. Furthermore, we demonstrate that restoration of SPOP expression inhibited SRC-3-mediated oncogenic signaling and tumorigenesis, thus positioning SPOP as a tumor suppressor.
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, USA. 01chao@gmail.com
authors.forename: C
authors.initials: C
authors.lastname: Li
authors.forename: J
authors.initials: J
authors.lastname: Ao
authors.forename: J
authors.initials: J
authors.lastname: Fu
authors.forename: D-F
authors.initials: DF
authors.lastname: Lee
authors.forename: J
authors.initials: J
authors.lastname: Xu
authors.forename: D
authors.initials: D
authors.lastname: Lonard
authors.forename: B W
authors.initials: BW
authors.lastname: O'Malley
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D048149:Casein Kinase 1 epsilon / Q000378:metabolism; D045744:Cell Line, Tumor; D044842:Cullin Proteins / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D056921:Nuclear Receptor Coactivator 3 / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D034741:RNA, Small Interfering / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: C503645:CUL3 protein, human; D002352:Carrier Proteins; D044842:Cullin Proteins; D009687:Nuclear Proteins; C479529:RBX1 protein, human; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C509761:SPOP protein, human; D025521:Tumor Suppressor Proteins; C538866:NCOA3 protein, human; D056921:Nuclear Receptor Coactivator 3; D044767:Ubiquitin-Protein Ligases; D048149:Casein Kinase 1 epsilon; D046988:Proteasome Endopeptidase Complex