Identification of a Src tyrosine kinase/SIAH2 E3 ubiquitin ligase pathway that regulates C/EBPδ expression and contributes to transformation of breast tumor cells.
The transcription factor CCAAT/enhancer-binding protein delta (C/EBPδ, CEBPD) is a tumor suppressor that is downregulated during breast cancer progression but may also promote metastasis. Here, we have investigated the mechanism(s) regulating C/EBPδ expression and its role in human breast cancer cells. We describe a novel pathway by which the tyrosine ... kinase Src downregulates C/EBPδ through the SIAH2 E3 ubiquitin ligase. Src phosphorylates SIAH2 in vitro and leads to tyrosine phosphorylation and activation of SIAH2 in breast tumor cell lines. SIAH2 interacts with C/EBPδ, but not C/EBPβ, and promotes its polyubiquitination and proteasomal degradation. Src/SIAH2-mediated inhibition of C/EBPδ expression supports elevated cyclin D1 levels, phosphorylation of retinoblastoma protein (Rb), motility, invasive properties, and survival of transformed cells. Pharmacological inhibition of Src family kinases by SKI-606 (bosutinib) induces C/EBPδ expression in an SIAH2-dependent manner, which is necessary for "therapeutic" responses to SKI-606 in vitro. Ectopic expression of degradation-resistant mutants of C/EBPδ, which do not interact with SIAH2 and/or cannot be polyubiquitinated, prevents full transformation of MCF-10A cells by activated Src (Src truncated at amino acid 531 [Src-531]) in vitro. These data reveal that C/EBPδ expression can be regulated at the protein level by oncogenic Src kinase signals through SIAH2, thus contributing to breast epithelial cell transformation.
Mesh Terms:
Breast, Breast Neoplasms, CCAAT-Enhancer-Binding Protein-delta, Cell Line, Tumor, Cell Transformation, Neoplastic, Cyclin D1, Female, Gene Expression Regulation, Neoplastic, Humans, Nuclear Proteins, RNA, Messenger, Signal Transduction, Ubiquitin-Protein Ligases, Ubiquitination, src-Family Kinases
Breast, Breast Neoplasms, CCAAT-Enhancer-Binding Protein-delta, Cell Line, Tumor, Cell Transformation, Neoplastic, Cyclin D1, Female, Gene Expression Regulation, Neoplastic, Humans, Nuclear Proteins, RNA, Messenger, Signal Transduction, Ubiquitin-Protein Ligases, Ubiquitination, src-Family Kinases
Mol. Cell. Biol.
Date: Jan. 01, 2012
PubMed ID: 22037769
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