Activation and repression of p21(WAF1/CIP1) transcription by RB binding proteins

Oncogene. 1998 Dec 31;17(26):3463-9. doi: 10.1038/sj.onc.1202240.

Abstract

The Cdk inhibitor p21(WAF1/CIP1) is a negative regulator of the cell cycle, although its expression is induced by a number of mitogens that promote cell proliferation. We have found that E2F1 and E2F3, transcription factors that activate genes required for cell cycle progression, are strong activators of the p21 promoter. In contrast, HBP1 (HMG-box protein-1), a novel retinoblastoma protein-binding protein, can repress the p21 promoter and inhibit induction of p21 expression by E2F. Both E2Fs and HBP1 regulate p21 transcription through cis-acting elements located between nucleotides -119 to +16 of the p21 promoter and the DNA binding domains of each of these proteins are required for activity. Sequences between -119 and -60 basepairs containing four Sp1 consensus elements and two noncanonical E2F binding sites are of major importance for E2F activation, although E2F1 and E2F3 differ in the extent of their ability to activate expression when this segment is deleted. The opposing effects of E2Fs and HBP1 on p21 promoter activity suggest that interplay between these factors may determine the level of p21 transcription in vivo.

Publication types

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

MeSH terms

  • Base Sequence
  • Binding Sites
  • Carrier Proteins*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / genetics*
  • Cyclins / metabolism*
  • DNA-Binding Proteins*
  • E2F Transcription Factors
  • E2F1 Transcription Factor
  • E2F2 Transcription Factor
  • E2F3 Transcription Factor
  • Gene Expression Regulation
  • Helix-Loop-Helix Motifs / genetics
  • High Mobility Group Proteins / genetics
  • High Mobility Group Proteins / metabolism
  • Humans
  • Molecular Sequence Data
  • Promoter Regions, Genetic
  • Regulatory Sequences, Nucleic Acid
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Retinoblastoma Protein / metabolism*
  • Retinoblastoma-Binding Protein 1
  • Sp1 Transcription Factor / metabolism
  • Transcription Factor DP1
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription, Genetic*
  • Tumor Cells, Cultured

Substances

  • CDKN1A protein, human
  • Carrier Proteins
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • DNA-Binding Proteins
  • E2F Transcription Factors
  • E2F1 Transcription Factor
  • E2F1 protein, human
  • E2F2 Transcription Factor
  • E2F3 Transcription Factor
  • HBP1 protein, human
  • High Mobility Group Proteins
  • Repressor Proteins
  • Retinoblastoma Protein
  • Retinoblastoma-Binding Protein 1
  • Sp1 Transcription Factor
  • Transcription Factor DP1
  • Transcription Factors