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Identification of a Src tyrosine kinase/SIAH2 E3 ubiquitin ligase pathway that regulates C/EBP? expression and contributes to transformation of breast tumor cells.
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| Author |
Tapasree Roysarkar,Shikha Sharan,Jun Wang,Snehalata A Pawar,Carrie A Cantwell,Peter F Johnson,Deborah K Morrison,Ju-Ming Wang,Esta Sterneck,Tapasree Roy Sarkar,Tapasree Roy Sarkar |
| Citation Information |
Molecular and cellular biology, 32: (2012) |
| Keywords |
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,src-Family Kinases,Ubiquitin-Protein Ligases,Ubiquitination |
| Related Products |
05-1050 |
| Pub Med ID |
22037769 |
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Abstract
The transcription factor CCAAT/enhancer-binding protein delta (C/EBP?, 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/EBP? expression and its role in human breast cancer cells. We describe a novel pathway by which the tyrosine kinase Src downregulates C/EBP? 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/EBP?, but not C/EBP?, and promotes its polyubiquitination and proteasomal degradation. Src/SIAH2-mediated inhibition of C/EBP? 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/EBP? 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/EBP?, 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/EBP? expression can be regulated at the protein level by oncogenic Src kinase signals through SIAH2, thus contributing to breast epithelial cell transformation.
