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C/EBP{delta} targets cyclin D1 for proteasome-mediated degradation via induction of CDC27/APC3 expression

Snehalata A Pawar1, Tapasree Roy Sarkar, Kuppusamy Balamurugan

  • 1Center for Cancer Research, National Cancer Institute, Frederick, MD 21702-1201, USA.

Proceedings of the National Academy of Sciences of the United States of America
|May 5, 2010
PubMed

Insights

CCAAT/enhancer binding protein delta (C/EBPdelta) promotes tumor suppression by increasing Cdc27, which degrades cyclin D1. This reveals a new mechanism for C/EBPdelta

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • CCAAT/enhancer binding protein delta (C/EBPdelta) is a transcription factor with known tumor suppressor functions.
  • The precise molecular mechanisms underlying C/EBPdelta's tumor suppressor activity remain largely unelucidated.
  • Understanding these mechanisms is crucial for developing targeted cancer therapies.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which C/EBPdelta exerts its tumor suppressor function.
  • To investigate the role of C/EBPdelta in regulating cell cycle proteins and the anaphase promoting complex/cyclosome (APC/C).
  • To determine if Cdc27, a subunit of APC/C, has potential tumor suppressor activity.

Main Methods:

  • Utilized C/EBPdelta knockout mouse embryo fibroblasts (MEFs) to assess protein level changes.
  • Employed gene silencing techniques (siRNA) in MCF-10A breast epithelial cells to study the effects of C/EBPdelta, Cdc27, and Cdh1.
  • Analyzed protein expression levels of key cell cycle regulators including cyclin D1, cyclin B1, Skp2, and Plk-1.
  • Investigated the degradation pathways of cyclin D1, comparing SCF and APC/C mediated ubiquitination.

Main Results:

  • C/EBPdelta induces the expression of Cdc27 (APC3), a subunit of the APC/C complex.
  • Induced Cdc27 leads to polyubiquitination and degradation of the pro-oncogenic cyclin D1.
  • C/EBPdelta also down-regulates cyclin B1, Skp2, and Plk-1.
  • Reduced Cdc27 levels were observed in C/EBPdelta knockout MEFs, correlating with increased cyclin D1.
  • Silencing C/EBPdelta, Cdc27, or Cdh1 in breast cells increased cyclin D1.
  • Cdc27 expression is downregulated in several breast cancer cell lines, suggesting its role as a tumor suppressor.
  • Cdc27 mediates an alternative degradation pathway for cyclin D1 via APC/C.

Conclusions:

  • C/EBPdelta functions as a tumor suppressor by upregulating Cdc27, which targets cyclin D1 for degradation.
  • Cdc27 itself may act as a tumor suppressor due to its downregulation in breast cancer cells.
  • These findings reveal a novel regulatory role for APC/C in controlling cyclin D1 stability and highlight C/EBPdelta's mechanism in cell cycle regulation.

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