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The novel p53 isoform "delta p53" is a misfolded protein and does not bind the p21 promoter site

Maria M García-Alai1, Henning Tidow, Eviatar Natan

  • 1Medical Research Council Centre for Protein Engineering, Cambridge CB2 0QH, United Kingdom.

Protein Science : a Publication of the Protein Society
|July 16, 2008
PubMed

Insights

The delta p53 (Delta p53) protein isoform is unstable and misfolded, preventing it from binding DNA. This explains its dominant-negative effect and lack of transcriptional activity in cancer research.

Area of Science:

  • Molecular Biology
  • Protein Structure and Function
  • Cancer Biology

Background:

  • The p53 tumor suppressor protein exists in multiple isoforms due to alternative splicing and mRNA editing.
  • One such isoform, delta p53 (Delta p53), arises from alternative splicing and is proposed to have transcriptional activity crucial for cell cycle control.

Purpose of the Study:

  • To investigate the structural basis for the proposed transcriptional activity of the Delta p53 isoform.
  • To elucidate the mechanism behind the dominant-negative effect of Delta p53.

Main Methods:

  • Analysis of protein structure and stability of the Delta p53 isoform.
  • In vitro studies of Delta p53 and flp53 complex formation and DNA binding.
  • Assessment of Delta p53 binding to the p21 promoter site.

Main Results:

  • The specific deletion of 66 residues in Delta p53 results in a misfolded and unstable protein.
  • Delta p53 readily forms soluble aggregates and fails to bind the p21 promoter.
  • Coexpressed Delta p53 and flp53 form a soluble complex with poor DNA binding.

Conclusions:

  • The structural instability and misfolding of Delta p53 explain its lack of transcriptional activity.
  • These findings provide a structural rationale for the dominant-negative impact of Delta p53 in cellular processes.

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