DNA damage-induced downregulation of Cdc25C is mediated by p53 via two independent mechanisms: one involves direct binding to the cdc25C promoter

Mol Cell. 2004 Dec 3;16(5):725-36. doi: 10.1016/j.molcel.2004.11.002.

Abstract

The Cdc25C phosphatase mediates cellular entry into mitosis. The cdc25C gene is a target for transcriptional downregulation by the tumor suppressor protein p53, and this repression can be shown to contribute to p53-dependent cell cycle arrest. Two independent mechanisms have been identified. One involves the direct binding of p53 to a site in the cdc25C promoter, and the second involves a CDE/CHR element. Both of these mediate p53-dependent repression at levels of p53 comparable to those produced by DNA damage. Three CCAAT elements in the cdc25C promoter that were previously implicated in p53-dependent repression fail to do so at physiologically relevant levels of p53. Repression of Cdc25C by p53 represents an additional mechanism for p53-dependent cell cycle arrest in response to DNA damage. Importantly, this is a clear demonstration of p53-mediated transcriptional downregulation that is dependent on sequence-specific DNA binding by p53.

Publication types

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

MeSH terms

  • Base Sequence
  • Binding Sites
  • Cell Cycle
  • Cell Cycle Proteins / chemistry*
  • Cell Cycle Proteins / metabolism
  • Cell Line
  • Cell Line, Tumor
  • Chromatin / metabolism
  • Cloning, Molecular
  • Cyclin-Dependent Kinase Inhibitor p21
  • DNA / metabolism
  • DNA Damage*
  • Dose-Response Relationship, Drug
  • Down-Regulation*
  • Doxorubicin / pharmacology
  • Genes, Reporter
  • Histone Deacetylases / metabolism
  • Humans
  • Immunoprecipitation
  • Models, Biological
  • Molecular Sequence Data
  • Mutation
  • Plasmids / metabolism
  • Proline / chemistry
  • Promoter Regions, Genetic*
  • Protein Binding
  • Protein Structure, Tertiary
  • Tetracycline / pharmacology
  • Time Factors
  • Transcription, Genetic
  • Transfection
  • Transgenes
  • Tumor Suppressor Protein p53 / metabolism*
  • Up-Regulation
  • cdc25 Phosphatases / chemistry*
  • cdc25 Phosphatases / metabolism

Substances

  • CDKN1A protein, human
  • Cell Cycle Proteins
  • Chromatin
  • Cyclin-Dependent Kinase Inhibitor p21
  • Tumor Suppressor Protein p53
  • Doxorubicin
  • DNA
  • Proline
  • CDC25C protein, human
  • cdc25 Phosphatases
  • Histone Deacetylases
  • Tetracycline