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Yeast As a Chassis for Developing Functional Assays to Study Human P53
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Evolution of the p53-MDM2 pathway.

Emma Åberg1, Fulvio Saccoccia1, Manfred Grabherr1

  • 1Department of Medical Biochemistry and Microbiology, Uppsala University, BMC Box 582, SE-75123, Uppsala, Sweden.

BMC Evolutionary Biology
|August 5, 2017
PubMed
Summary

The ancient p53/p63/p73-MDM signaling pathway co-evolved across animal phyla. This study builds phylogenetic trees of p53/p63/p73 and MDM proteins, revealing their linked evolutionary history.

Keywords:
Co-evolutionMDMPhylogenyp53

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Area of Science:

  • Evolutionary biology
  • Molecular biology
  • Genomics

Background:

  • The p53 signaling pathway is crucial for cell fate and tumor suppression.
  • It involves p53, its paralogs (p63, p73), and regulators (MDM2, MDM4).
  • This ancient system is present across animal phyla, but comprehensive phylogenetic trees are lacking.

Purpose of the Study:

  • To investigate the evolutionary history of the p53/p63/p73 protein family and their regulators.
  • To focus on the co-evolution of the transactivation domain (TAD) and the p53/p63/p73-binding domain (p53/p63/p73BD) of MDM2.
  • To construct accurate phylogenetic trees incorporating both vertebrate and invertebrate species.

Main Methods:

  • Phylogenetic analysis of p53/p63/p73 and MDM proteins.
  • Focus on species retaining the interacting TAD and p53/p63/p73BD domains.
  • Construction of phylogenetic trees based on 183 p53/p63/p73 and 98 MDM species.

Main Results:

  • A strong co-evolutionary link was identified between the TAD and p53/p63/p73BD.
  • Loss of one domain often leads to the loss of function and eventual disappearance of the other.
  • Phylogenetic trees accurately reflect species evolution and suggest the p53/p63/p73 and MDM families arose from whole genome duplications.

Conclusions:

  • The p53/p63/p73-MDM signaling pathway has a deep evolutionary origin in metazoans.
  • This pathway has undergone tight co-evolution or lineage-specific loss.
  • Understanding this co-evolution provides insights into the conservation and diversification of this critical pathway.