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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / genetics
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Adenocarcinoma / metabolism
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Animals
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism
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Carrier Proteins / metabolism
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Casein Kinase 1 epsilon / metabolism
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Cell Line, Tumor
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Cullin Proteins / metabolism*
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Female
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Gene Expression Regulation, Neoplastic
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Humans
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Mice
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Mice, Nude
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Nuclear Receptor Coactivator 3 / metabolism*
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Proteasome Endopeptidase Complex / metabolism
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Proteolysis
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RNA, Small Interfering / metabolism
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Signal Transduction*
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Tumor Suppressor Proteins / metabolism*
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Ubiquitin-Protein Ligases / metabolism*
Substances
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CUL3 protein, human
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Carrier Proteins
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Cullin Proteins
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Nuclear Proteins
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RBX1 protein, human
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RNA, Small Interfering
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Repressor Proteins
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SPOP protein, human
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Tumor Suppressor Proteins
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NCOA3 protein, human
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Nuclear Receptor Coactivator 3
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Ubiquitin-Protein Ligases
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Casein Kinase 1 epsilon
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Proteasome Endopeptidase Complex