Tumor-suppressor role for the SPOP ubiquitin ligase in signal-dependent proteolysis of the oncogenic co-activator SRC-3/AIB1

Oncogene. 2011 Oct 20;30(42):4350-64. doi: 10.1038/onc.2011.151. Epub 2011 May 16.

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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / metabolism
  • Animals
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Carrier Proteins / metabolism
  • Casein Kinase Iepsilon / metabolism
  • Cell Line, Tumor
  • Cullin Proteins / metabolism*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mice
  • Mice, Nude
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Nuclear Receptor Coactivator 3 / metabolism*
  • Proteasome Endopeptidase Complex / metabolism
  • Proteolysis
  • RNA, Small Interfering / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Signal Transduction*
  • Tumor Suppressor Proteins / metabolism*
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • CUL3 protein, human
  • Carrier Proteins
  • Cullin Proteins
  • Nuclear Proteins
  • RBX1 protein, human
  • RNA, Small Interfering
  • Repressor Proteins
  • SPOP protein, human
  • Tumor Suppressor Proteins
  • NCOA3 protein, human
  • Nuclear Receptor Coactivator 3
  • Ubiquitin-Protein Ligases
  • Casein Kinase Iepsilon
  • Proteasome Endopeptidase Complex