E2F2 and CREB cooperatively regulate transcriptional activity of cell cycle genes

Nucleic Acids Res. 2013 Dec;41(22):10185-98. doi: 10.1093/nar/gkt821. Epub 2013 Sep 12.


E2F2 is essential for the maintenance of T lymphocyte quiescence. To identify the full set of E2F2 target genes, and to gain further understanding of the role of E2F2 in transcriptional regulation, we have performed ChIP-chip analyses across the genome of lymph node-derived T lymphocytes. Here we show that during quiescence, E2F2 binds the promoters of a large number of genes involved in DNA metabolism and cell cycle regulation, concomitant with their transcriptional silencing. A comparison of ChIP-chip data with expression profiling data on resting E2f2(-)(/)(-) T lymphocytes identified a subset of 51 E2F2-specific target genes, most of which are upregulated on E2F2 loss. Luciferase reporter assays showed a retinoblastoma-independent role for E2F2 in the negative regulation of these target genes. Importantly, we show that the DNA binding activity of the transcription factor CREB contributes to E2F2-mediated repression of Mcm5 and Chk1 promoters. siRNA-mediated CREB knockdown, expression of a dominant negative KCREB mutant or disruption of CREB binding by mutating a CRE motif on Mcm5 promoter, relieved E2F2-mediated transcriptional repression. Taken together, our data uncover a new regulatory mechanism for E2F-mediated transcriptional control, whereby E2F2 and CREB cooperate in the transcriptional repression of a subset of E2F2 target genes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • E2F2 Transcription Factor / genetics
  • E2F2 Transcription Factor / metabolism*
  • Gene Expression Regulation*
  • Genes, cdc*
  • Humans
  • Mice
  • Mice, Knockout
  • Promoter Regions, Genetic
  • Repressor Proteins / metabolism
  • T-Lymphocytes / metabolism
  • Transcription, Genetic*


  • Creb1 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • E2F2 Transcription Factor
  • E2f2 protein, mouse
  • Repressor Proteins