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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

Use of genetic suppressor elements to dissect distinct biological effects of separate p53 domains

V S Ossovskaya1, I A Mazo, M V Chernov

  • 1Department of Genetics, University of Illinois, Chicago, IL 60607, USA.

Proceedings of the National Academy of Sciences of the United States of America
|September 17, 1996
PubMed

Insights

Researchers isolated genetic suppressor elements (GSEs) from p53 cDNA fragments to study its tumor suppressor functions. Different GSE classes revealed distinct roles for p53 domains in cell immortalization, transformation, and DNA damage response.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Biology

Background:

  • The p53 protein is a critical tumor suppressor regulating cell growth and preventing cancer.
  • Mutations in p53 lead to cellular changes like immortalization, neoplastic transformation, and drug resistance.

Purpose of the Study:

  • To dissect the distinct functions of the p53 protein by identifying specific domains responsible for its various cellular roles.
  • To investigate the role of the 3'-untranslated region of p53 mRNA in regulating p53 activity.

Main Methods:

  • Isolation of genetic suppressor elements (GSEs) from a retroviral library of random rat p53 cDNA fragments.
  • Categorization of GSEs into four classes based on their corresponding p53 domains (transactivator, DNA-binding, C-terminal) and the 3'-untranslated region.
  • Assay of GSEs for their ability to induce phenotypes such as cell immortalization, transformation (in cooperation with Ras), and drug resistance.

Main Results:

  • GSEs from all four classes promoted immortalization of primary rodent embryo fibroblasts.
  • GSEs from the transactivator (Class I) and C-terminal (Class III) domains cooperated with activated Ras to induce neoplastic transformation.
  • GSEs from the C-terminal domain (Class III) conferred resistance to etoposide and inhibited p53 transcriptional activity.

Conclusions:

  • Different functional domains of p53 are involved in distinct cellular processes, including senescence control, DNA damage response, and transformation.
  • The 3'-untranslated region of p53 mRNA plays a regulatory role in p53 function.

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