Human homologue of yeast Rad23 protein A interacts with p300/cyclic AMP-responsive element binding (CREB)-binding protein to down-regulate transcriptional activity of p53

Cancer Res. 2001 Jan 1;61(1):64-70.

Abstract

The tumor suppressor protein p53 regulates various cellular responses to DNA damage and plays a significant role in DNA repair. The nuclear p300/cyclic AMP-responsive element binding (CREB)-binding protein (CBP) proteins act as coactivators in supporting the transcription function of p53. We examined the role of the human homologue of yeast Rad23 protein A (hHR23A), one of the two human homologues of the Saccharomyces cerevisiae nucleotide excision repair gene product Rad23, in the p300/CBP-associated regulation of p53 activity. Overexpression of wild-type hHR23A inhibits the p53 transcriptional activity and results in a decreased steady-state protein level of cellular p53. The inhibitory effect of hHR23A can be overcome by the concomitant expression of p300, CBP, and p300 segments harboring C/H1 domain and neutralized by the coexpression of HIV accessory protein Vpr, which binds COOH terminus of hHR23A/B. Additionally, hHR23A was shown to interact in vitro and in vivo with p300 segments harboring C/H1 domain. These studies provide evidence for the involvement of hHR23A in the regulation of p53 activity through p300/CBP. Although the precise direct role of hHR23 proteins in regulation of p53 and DNA repair remains to be elucidated, our data suggest that the interaction between hHR23A and p300/CBP has important implications in cross-talk between the p53 pathway and DNA repair.

Publication types

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

MeSH terms

  • Animals
  • Cyclic AMP Response Element-Binding Protein / biosynthesis
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Cyclic AMP Response Element-Binding Protein / physiology*
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / biosynthesis
  • DNA Repair Enzymes
  • DNA-Binding Proteins / biosynthesis
  • DNA-Binding Proteins / metabolism
  • DNA-Binding Proteins / physiology*
  • Down-Regulation / physiology
  • E1A-Associated p300 Protein
  • Gene Expression Regulation / physiology
  • Humans
  • Mice
  • Nuclear Proteins / biosynthesis
  • Nuclear Proteins / metabolism
  • Nuclear Proteins / physiology*
  • Protein Binding
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins / physiology
  • Proto-Oncogene Proteins c-mdm2
  • Trans-Activators / biosynthesis
  • Trans-Activators / metabolism
  • Trans-Activators / physiology*
  • Transcription, Genetic / physiology*
  • Transcriptional Activation / physiology
  • Tumor Suppressor Protein p53 / antagonists & inhibitors
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Protein p53 / physiology*

Substances

  • CDKN1A protein, human
  • Cdkn1a protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • DNA-Binding Proteins
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Trans-Activators
  • Tumor Suppressor Protein p53
  • RAD23A protein, human
  • E1A-Associated p300 Protein
  • Ep300 protein, mouse
  • MDM2 protein, human
  • Mdm2 protein, mouse
  • Proto-Oncogene Proteins c-mdm2
  • DNA Repair Enzymes