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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

Activation of the cryptic DNA binding function of mutant forms of p53

T R Hupp1, D W Meek, C A Midgley

  • 1Cancer Research Campaign Laboratories, Dundee, UK.

Nucleic Acids Research
|July 11, 1993
PubMed

Insights

Mutant p53 proteins retain latent DNA binding capabilities, but their activation is sensitive to specific regulatory pathways. This suggests a signaling pathway defect contributes to the loss of p53 tumor suppressor function.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Protein Biochemistry

Background:

  • Wild-type p53 protein forms a latent complex, requiring specific activators for DNA binding.
  • Common p53 mutations can affect its DNA binding and regulatory functions.

Purpose of the Study:

  • To investigate the impact of p53 mutations on its latent DNA binding activity.
  • To explore the regulatory mechanisms of mutant p53 activation.

Main Methods:

  • Utilized an optimized system to link post-translational modification to p53 DNA binding activation.
  • Examined activation of wild-type and mutant p53 using specific antibodies (PAb421) and proteins (DnaK, casein kinase II).
  • Assessed the requirement of a reactive sulfhydryl group for DNA binding.

Main Results:

  • Two mutant p53 forms were activated by PAb421 and DnaK but not casein kinase II.
  • Mutant p53 activation by casein kinase II was impaired, suggesting altered allosteric regulation.
  • A reactive sulfhydryl group is essential for DNA binding in both wild-type and activated mutant p53.

Conclusions:

  • Certain p53 mutants retain the intrinsic machinery for sequence-specific DNA binding.
  • Inactivation of a specific signaling pathway may underlie the loss of p53 tumor suppressor function.
  • Mutant p53 responsiveness to casein kinase II phosphorylation is compromised.

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