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Yeast As a Chassis for Developing Functional Assays to Study Human P53
14:57

Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

Stimulus-specific transcriptional regulation within the p53 network

Aaron Joseph Donner1, Jennifer Michelle Hoover, Stephanie Aspen Szostek

  • 1Department of Molecular, Cellular and Developmental Biology, University of Colorado at Boulder, Boulder, Colorado, USA.

Cell Cycle (Georgetown, Tex.)
|October 25, 2007
PubMed

Insights

The p53 protein

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • The p53 protein network regulates stress responses, including cell cycle arrest and apoptosis.
  • Differential activation of p53 target genes is crucial for stress-specific outcomes but remains unclear.
  • Understanding these mechanisms is vital for cancer therapy development.

Purpose of the Study:

  • To investigate how distinct p53 target genes are differentially activated by various stimuli.
  • To elucidate the role of transcriptional coregulators in mediating stimulus-specific p53 target gene expression.
  • To analyze the p53 transcriptional program in response to DNA damage (UVC, doxorubicin) and non-genotoxic activation (Nutlin-3).

Main Methods:

  • Quantitative gene expression analysis to classify p53 target genes.
  • Chromatin immunoprecipitation (ChIP) to analyze p53 binding and histone acetylation at the p21 locus.
  • Investigation of the human Mediator complex's role in p21 transcription.

Main Results:

  • p53 target genes were grouped into three classes based on activation profiles under different stress conditions.
  • The cyclin-dependent kinase inhibitor p21 (CDK-inhibitor p21) was activated during cell cycle arrest but not UVC-induced apoptosis.
  • Stimulus-specific coregulators, particularly the Mediator complex CDK-module, modulate p53-dependent p21 transcription.

Conclusions:

  • The Mediator complex CDK-module acts as a stimulus-specific positive coregulator for p53 target genes like p21.
  • Differential gene activation within the p53 network is controlled by downstream coregulators, enabling distinct cellular responses.
  • This provides insight into the precise control of stress responses mediated by the p53 network.

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