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

Published on: August 4, 2019

P53 in blind subterranean mole rats--loss-of-function versus gain-of-function activities on newly cloned Spalax

A Avivi1, O Ashur-Fabian, A Joel

  • 1Laboratory of Animal Molecular Evolution, Institute of Evolution, University of Haifa, Mount Carmel, Haifa, Israel. aaron@research.haifa.ac.il

Oncogene
|October 18, 2006
PubMed

Insights

Blind mole rats (Spalax) possess a unique p53 mutation that suppresses apoptosis and promotes cell cycle arrest, aiding survival in low-oxygen conditions. This adaptation mirrors cancer cell evolution, favoring DNA repair over programmed cell death.

Area of Science:

  • Molecular Biology
  • Genetics
  • Evolutionary Biology

Background:

  • The p53 tumor suppressor gene regulates cellular stress responses, including apoptosis and growth arrest.
  • Blind subterranean mole rats (Spalax) are a model for hypoxia tolerance.
  • Spalax p53 exhibits an Arg174Lys substitution in its DNA-binding domain.

Purpose of the Study:

  • To investigate the functional impact of the Spalax p53 Arg174Lys substitution on gene transcription.
  • To compare Spalax p53-responsive elements with those of other species.
  • To understand the evolutionary adaptation of p53 in hypoxia-tolerant Spalax.

Main Methods:

  • Cloning of Spalax apaf1 promoter and mdm2 intronic regions.
  • Comparison of Spalax-responsive elements with human, mouse, and rat sequences.
  • Assessing the transcriptional activity of Spalax and human Arg174Lys-mutated p53 on target genes.

Main Results:

  • Spalax and human-mutated p53 failed to induce apaf1 transcription.
  • Spalax and human-mutated p53 enhanced mdm2 transcription.
  • The Arg174Lys substitution alters p53's regulatory effects on apoptosis and cell cycle genes.

Conclusions:

  • Spalax has evolved hypoxia-adaptive mechanisms involving p53.
  • These adaptations involve reduced apoptosis and enhanced cell cycle arrest/DNA repair.
  • The Spalax p53 alterations resemble those seen in cancer cells, favoring survival mechanisms.

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