The molecular basis of E2F-1/DP-1-induced S-phase entry and apoptosis

Cell Growth Differ. 1996 Jun;7(6):689-97.

Abstract

The transcription factor E2F plays a critical role in the G1 to S transition. E2F is a heterodimer formed by members of the E2F and DP families of DNA-binding proteins. Ectopic expression of E2F-1, the first member of the E2F family identified, is sufficient to cause quiescent cells to enter S phase. Thus, the biological significance of the interaction of E2F-1 with its DP protein partner, DP-1, was unclear. Here, we report on the role of DP-1 in the mediation of E2F-induced S-phase entry and apoptosis. Cells inducible for DP-1, E2F-1, or both were established and characterized. Ectopic expression of DP-1 alone fails to promote cell cycle entry, even when the potent transactivation domain of human papillomavirus-VP16 is fused to the DNA-binding domain of DP-1. In contrast, coexpression of DP-1 and E2F-1 results in greater loss of G1 regulation and significantly more apoptosis than does E2F-1 alone. Using clones co-inducible for DP-1 and E2F-1, expression of potential target genes of E2F activity that may account for its ability to induce S-phase entry was also examined. Induction of E2F-1/DP-1 resulted in increased expression and activity of cyclins A and E, as well as CDK2, prior to S-phase entry. Cyclin D and CDK4, however, were not induced. Phosphorylation of the retinoblastoma protein is also increased following induction of E2F-1/DP-1, suggesting that E2F can feed-back on the retinoblastoma protein, presumably through activation of cyclin A- and/or E-associated kinase activity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • Carrier Proteins*
  • Cell Cycle Proteins / physiology*
  • Clone Cells
  • Cyclins / physiology
  • DNA-Binding Proteins / physiology*
  • E2F Transcription Factors
  • E2F1 Transcription Factor
  • Gene Expression Regulation / physiology
  • Papillomaviridae / genetics
  • Phosphorylation
  • Protein Structure, Tertiary
  • Rats
  • Retinoblastoma-Binding Protein 1
  • S Phase / physiology*
  • Transcription Factor DP1
  • Transcription Factors / biosynthesis
  • Transcription Factors / physiology*
  • Transcriptional Activation

Substances

  • Carrier Proteins
  • Cell Cycle Proteins
  • Cyclins
  • DNA-Binding Proteins
  • E2F Transcription Factors
  • E2F1 Transcription Factor
  • E2f1 protein, rat
  • Retinoblastoma-Binding Protein 1
  • Transcription Factor DP1
  • Transcription Factors