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Identification of a Src Tyrosine Kinase/SIAH2 E3 Ubiquitin Ligase Pathway That Regulates C/EBP delta Expression and Contributes to Transformation of Breast Tumor Cells

  1. Author:
    Sarkar, T. R.
    Sharan, S.
    Wang, J.
    Pawar, S. A.
    Cantwell, C. A.
    Johnson, P. F.
    Morrison, D. K.
    Wang, J. M.
    Sterneck, E.

  2. Author Address

    [Sarkar, Tapasree Roy; Sharan, Shikha; Wang, Jun; Pawar, Snehalata A.; Morrison, Deborah K.; Sterneck, Esta] NCI, Lab Cell & Dev Signaling, Ctr Canc Res, Frederick, MD 21701 USA. [Cantwell, Carrie A.; Johnson, Peter F.] NCI, Lab Canc Prevent, Ctr Canc Res, Frederick, MD 21701 USA. [Wang, Ju-Ming] Natl Cheng Kung Univ, Coll Biosci & Biotechnol, Inst Bioinformat & Biosignal Transduct, Tainan 70101, Taiwan.;Sterneck, E (reprint author), NCI, Lab Cell & Dev Signaling, Ctr Canc Res, Frederick, MD 21701 USA;sternecg@mail.nih.gov
    1. Year: 2012
    2. Date: Jan
  2. Journal: Molecular and Cellular Biology
    1. 32
    2. 2
    3. Pages: 320-332
  4. Type of Article: Article
  5. ISSN: 0270-7306
  1. Abstract:

    The transcription factor CCAAT/enhancer-binding protein delta (C/EBP delta, 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 delta expression and its role in human breast cancer cells. We describe a novel pathway by which the tyrosine kinase Src downregulates C/EBP delta 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 delta, but not C/EBP beta, and promotes its polyubiquitination and proteasomal degradation. Src/SIAH2-mediated inhibition of C/EBP delta expression supports elevated cydin 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 delta 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 delta, 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 delta expression can be regulated at the protein level by oncogenic Src kinase signals through SIAH2, thus contributing to breast epithelial cell transformation.

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  2. DOI: 10.1128/mcb.05790-11
  3. View record in Web of Science®
  4. WOS: 000299020100008

Library Notes

  1. Fiscal Year: FY2011-2012
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