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Ezh2 reduces the ability of HDAC1-dependent pRb2/p130 transcriptional repression of cyclin A.

The polycomb group (PcG) proteins are known to be involved in maintaining the silenced state of several developmentally regulated genes. Enhancer of zeste homolog 2 (Ezh2), a member of this large protein family, has also been shown to be deregulated in different tumor types and its role, both as a potential primary effector and as a mediator of tumorigenesis, has become a subject of increased interest. We observed that Ezh2 binds to pRb2/p130, a member of the retinoblastoma family; as such, we were led to consider the possible ability of Ezh2 to modulate cell cycle progression. Both Ezh2 and pRb2/p130 repress gene expression by recruiting histone deacetylase (HDAC1), which decreases DNA accessibility for activating transcription factors. Additionally, we observed that Ezh2 interacts with the C-terminal region of pRb2/p130, essential for interaction with HDAC1. We show that Ezh2 is able to reverse pRb2/p130-HDAC1-mediated repression of the cyclin A promoter. This indicates a functional role of this complex in regulating cyclin A expression, known to be crucial in mediating cell cycle advancement. We also detected a significant decrease in the retention of HDAC1 activity associated with pRb2/p130 when Ezh2 was overexpressed. Finally, electromobility shift assays (EMSA) demonstrated that overexpression of Ezh2 caused the abrogation of the pRb2/p130-HDAC1 complex on the cyclin A promoter. These data, taken together, suggest that Ezh2 competes with HDAC1 in binding to pRb2/p130, disrupting their occupancy on the cyclin A promoter. In this study, we propose a new mechanism for the functional inactivation of pRb2/p130 that ultimately contributes to cell cycle progression and malignant transformation.

Pubmed ID: 15077161


  • Tonini T
  • Bagella L
  • D'Andrilli G
  • Claudio PP
  • Giordano A



Publication Data

June 17, 2004

Associated Grants


Mesh Terms

  • 3T3 Cells
  • Animals
  • Breast Neoplasms
  • Cell Line
  • Cell Line, Tumor
  • Cyclin A
  • DNA-Binding Proteins
  • Female
  • Histone Deacetylase 1
  • Histone Deacetylases
  • Histone-Lysine N-Methyltransferase
  • Humans
  • Male
  • Mice
  • Plasmids
  • Polycomb Repressive Complex 2
  • Prostate
  • Prostatic Neoplasms
  • Proteins
  • Retinoblastoma-Like Protein p130
  • Transcription Factors
  • Transcription, Genetic