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

Proc Natl Acad Sci U S A. 2010 May 18;107(20):9210-5. doi: 10.1073/pnas.0913813107. Epub 2010 May 3.

Abstract

The transcription factor CCAAT/enhancer binding protein delta (C/EBPdelta, CEBPD, NFIL-6beta) has tumor suppressor function; however, the molecular mechanism(s) by which C/EBPdelta exerts its effect are largely unknown. Here, we report that C/EBPdelta induces expression of the Cdc27 (APC3) subunit of the anaphase promoting complex/cyclosome (APC/C), which results in the polyubiquitination and degradation of the prooncogenic cell cycle regulator cyclin D1, and also down-regulates cyclin B1, Skp2, and Plk-1. In C/EBPdelta knockout mouse embryo fibroblasts (MEF) Cdc27 levels were reduced, whereas cyclin D1 levels were increased even in the presence of activated GSK-3beta. Silencing of C/EBPdelta, Cdc27, or the APC/C coactivator Cdh1 (FZR1) in MCF-10A breast epithelial cells increased cyclin D1 protein expression. Like C/EBPdelta, and in contrast to cyclin D1, Cdc27 was down-regulated in several breast cancer cell lines, suggesting that Cdc27 itself may be a tumor suppressor. Cyclin D1 is a known substrate of polyubiquitination complex SKP1/CUL1/F-box (SCF), and our studies show that Cdc27 directs cyclin D1 to alternative degradation by APC/C. These findings shed light on the role and regulation of APC/C, which is critical for most cellular processes.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apc3 Subunit, Anaphase-Promoting Complex-Cyclosome
  • Blotting, Western
  • Breast Neoplasms / metabolism*
  • CCAAT-Enhancer-Binding Protein-delta / genetics
  • CCAAT-Enhancer-Binding Protein-delta / metabolism*
  • Cell Cycle Proteins / metabolism*
  • Cell Line, Tumor
  • Cyclin B1 / metabolism
  • Cyclin D1 / metabolism*
  • Gene Expression Regulation, Neoplastic / genetics*
  • Gene Expression Regulation, Neoplastic / physiology
  • Immunoprecipitation
  • Mice
  • Mice, Knockout
  • Microscopy, Fluorescence
  • Polo-Like Kinase 1
  • Proteasome Endopeptidase Complex / metabolism*
  • Protein Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • S-Phase Kinase-Associated Proteins / metabolism

Substances

  • Apc3 Subunit, Anaphase-Promoting Complex-Cyclosome
  • CDC27 protein, mouse
  • Ccnb1 protein, mouse
  • Cebpd protein, mouse
  • Cell Cycle Proteins
  • Cyclin B1
  • Proto-Oncogene Proteins
  • S-Phase Kinase-Associated Proteins
  • Cyclin D1
  • CCAAT-Enhancer-Binding Protein-delta
  • Protein Serine-Threonine Kinases
  • Proteasome Endopeptidase Complex