Identification of a Src tyrosine kinase/SIAH2 E3 ubiquitin ligase pathway that regulates C/EBPδ expression and contributes to transformation of breast tumor cells

Tapasree Roy Sarkar, Shikha Sharan, Jun Wang, Snehalata A. Pawara, Carrie A. Cantwell, Peter F. Johnson, Deborah K. Morrison, Ju-Ming Wang, Esta Sterneck

研究成果: Article

41 引文 (Scopus)

摘要

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.

原文English
頁(從 - 到)320-332
頁數13
期刊Molecular and Cellular Biology
32
發行號2
DOIs
出版狀態Published - 2012 一月 1

指紋

Ubiquitin-Protein Ligases
src-Family Kinases
Breast Neoplasms
CCAAT-Enhancer-Binding Protein-delta
Down-Regulation
Phosphorylation
Retinoblastoma Protein
Cyclin D1
Protein C
Tumor Cell Line
Tyrosine
Cell Survival
Breast
Transcription Factors
Epithelial Cells
Pharmacology
Neoplasm Metastasis
Amino Acids
In Vitro Techniques
bosutinib

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

引用此文

Sarkar, Tapasree Roy ; Sharan, Shikha ; Wang, Jun ; Pawara, Snehalata A. ; Cantwell, Carrie A. ; Johnson, Peter F. ; Morrison, Deborah K. ; Wang, Ju-Ming ; Sterneck, Esta. / Identification of a Src tyrosine kinase/SIAH2 E3 ubiquitin ligase pathway that regulates C/EBPδ expression and contributes to transformation of breast tumor cells. 於: Molecular and Cellular Biology. 2012 ; 卷 32, 編號 2. 頁 320-332.
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Identification of a Src tyrosine kinase/SIAH2 E3 ubiquitin ligase pathway that regulates C/EBPδ expression and contributes to transformation of breast tumor cells. / Sarkar, Tapasree Roy; Sharan, Shikha; Wang, Jun; Pawara, Snehalata A.; Cantwell, Carrie A.; Johnson, Peter F.; Morrison, Deborah K.; Wang, Ju-Ming; Sterneck, Esta.

於: Molecular and Cellular Biology, 卷 32, 編號 2, 01.01.2012, p. 320-332.

研究成果: Article

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