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Inhibition of p53-mediated transactivation and cell cycle arrest by E1A through its p300/CBP-interacting region

K Somasundaram1, W S El-Deiry

  • 1Department of Medicine and Genetics, University of Pennsylvania School of Medicine and Comprehensive Cancer Center, Philadelphia 19104, USA.

Oncogene
|March 6, 1997
PubMed

Insights

The adenovirus E1A oncoprotein inhibits p53-mediated cellular responses by binding to p300/CBP, not Rb. This interaction blocks p53

Area of Science:

  • Molecular Biology
  • Virology
  • Oncology

Background:

  • Adenovirus E1A oncoprotein is crucial for cellular transformation.
  • E1A interacts with cellular proteins including p300/CBP and Retinoblastoma tumor suppressor (Rb).
  • p53 is a key tumor suppressor protein that regulates cellular responses to DNA damage and oncogenic stress.

Purpose of the Study:

  • To elucidate the specific domains of adenovirus E1A responsible for inhibiting p53-mediated transactivation.
  • To determine the roles of p300/CBP and Rb binding in E1A's inhibition of p53.
  • To investigate how E1A affects p53-dependent cellular responses, such as cell cycle checkpoints.

Main Methods:

  • Utilizing E1A mutants deficient in binding to p300/CBP or Rb.
  • Assessing p53-mediated transactivation using reporter assays and endogenous p53 target genes (p21WAF1/CIP1, MDM2).
  • Evaluating the impact of E1A on DNA-damage activated p53-dependent cell cycle checkpoints.
  • Investigating the effect of exogenous p300 and CBP on E1A's inhibition of p53.

Main Results:

  • The p300/CBP-binding domain of E1A, not the Rb-binding domain, mediates the inhibition of p53-mediated transactivation.
  • E1A mutants lacking Rb interaction but retaining p300/CBP binding inhibited p53 activity and DNA-damage induced checkpoints.
  • E1A mutants unable to bind p300/CBP stabilized p53 but failed to repress p21 expression, dissociating p53 stabilization from repression.
  • Exogenous p300/CBP could rescue E1A-mediated inhibition of p53 transcription.

Conclusions:

  • Adenovirus E1A inhibits p53-dependent cellular responses primarily through its interaction with p300/CBP.
  • This inhibition affects critical cellular processes like DNA replication control following viral infection.
  • The findings differentiate the roles of p300/CBP and Rb binding in E1A's oncogenic functions.

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