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Transcription factor TAFII250 promotes Mdm2-dependent turnover of p53

N Allende-Vega1, M K Saville, D W Meek

  • 1Biomedical Research Centre, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.

Oncogene
|January 24, 2007
PubMed

Insights

TAFII250 regulates the tumor suppressor p53 by influencing Mdm2, a key protein in p53 degradation. This study reveals how TAFII250 impacts Mdm2 activity, affecting p53 levels and cell cycle arrest.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Biology

Background:

  • The p53 tumor suppressor is primarily regulated by Mdm2, an E3 ubiquitin ligase responsible for p53 ubiquitylation and degradation.
  • Agents that induce p53 often inhibit transcription, suggesting a link between transcriptional malfunction and p53 pathway activation.
  • Mdm2 interacts with TAFII250, a component of the general transcription factor TFIID.

Purpose of the Study:

  • To investigate the mechanism by which TAFII250 influences p53 levels.
  • To elucidate the role of TAFII250 in regulating Mdm2 activity and its impact on p53 degradation.
  • To explore the connection between TAFII250, Mdm2, and p53 in the context of transcriptional integrity.

Main Methods:

  • Utilized ts13 cells expressing a temperature-sensitive mutant of TAFII250 to study p53 induction and cell cycle arrest.
  • Investigated the effect of TAFII250 on p53 ubiquitylation and degradation.
  • Analyzed the interaction between TAFII250 and Mdm2, focusing on Mdm2 auto-ubiquitylation and p53-Mdm2 association.

Main Results:

  • TAFII250 was shown to stimulate the ubiquitylation and degradation of p53 in an Mdm2-dependent manner.
  • TAFII250's action requires the acidic domain of Mdm2.
  • TAFII250 downregulates Mdm2 auto-ubiquitylation, leading to Mdm2 stabilization and enhanced p53-Mdm2 association.

Conclusions:

  • TAFII250 directly influences p53 levels through Mdm2 regulation.
  • These findings support the hypothesis that p53 turnover is coupled to the integrity of RNA polymerase II transcription.
  • A novel pathway for TAFII250-mediated control of p53 stability has been identified.

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