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Identification of a minimal transforming domain of p53: negative dominance through abrogation of sequence-specific

E Shaulian1, A Zauberman, D Ginsberg

  • 1Department of Chemical Immunology, Weizmann Institute of Science, Rehovot, Israel.

Molecular and Cellular Biology
|December 1, 1992
PubMed

Insights

Mutant p53 proteins drive cancer by forming complexes with normal p53. This study shows that even without mutations, p53 fragments can transform cells by disrupting normal p53 function.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Mutations in the p53 tumor suppressor gene are common in human cancers.
  • Many p53 mutants exhibit in vitro transforming activity.
  • In transformed cells, mutant p53 protein oligomerizes with endogenous wild-type p53.

Purpose of the Study:

  • To investigate the role of p53 oligomerization in cellular transformation.
  • To determine if p53 oligomerization is sufficient for transformation.
  • To elucidate the mechanism by which p53 mutants mediate transformation.

Main Methods:

  • Generation of p53 miniproteins containing C-terminal portions.
  • Assessment of transforming activity of p53 miniproteins in vitro.
  • Analysis of oligomerization of miniproteins with wild-type p53.
  • Evaluation of the effect of miniproteins on wild-type p53 DNA binding.

Main Results:

  • p53 miniproteins, lacking point mutations, demonstrated significant transforming activity.
  • Transforming activity correlated with the ability to oligomerize with wild-type p53.
  • Miniproteins abrogated sequence-specific DNA binding of coexpressed wild-type p53.
  • Oligomerization led to the generation of DNA binding-incompetent p53 complexes.

Conclusions:

  • p53-mediated cellular transformation can occur through a dominant-negative mechanism.
  • Oligomerization of p53, even without mutations, is crucial for transformation.
  • The formation of DNA binding-incompetent p53 oligomers is a key event in transformation.

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