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p53 Activity Dominates That of p73 upon Mdm4 Loss in Development and Tumorigenesis

Mehrnoosh Tashakori1, Yun Zhang2, Shunbin Xiong2

  • 1Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas. The University of Texas Graduate School of Biomedical Sciences, Program in Genes and Development.

Molecular Cancer Research : MCR
|November 4, 2015
PubMed
Abstract

Insights

The Mdm4-p73 interaction does not significantly impact development or cancer, as p53 plays a dominant role. Loss of p73 did not rescue Mdm4-deficient embryonic lethality or brain abnormalities.

Area of Science:

  • Molecular Biology
  • Developmental Biology
  • Cancer Research

Background:

  • Mdm4 is a negative regulator of the p53 tumor suppressor.
  • Mdm4 loss causes embryonic lethality dependent on p53.
  • Mdm4 binds p73 with higher affinity than p53.

Purpose of the Study:

  • To investigate the in vivo significance of the Mdm4-p73 interaction during embryogenesis and tumorigenesis.

Main Methods:

  • Genetic analysis of Mdm4 and p73 interactions in mouse models.
  • Phenotypic characterization of Mdm4-deficient embryos with varying p73 and p53 genotypes.
  • Tumorigenesis studies comparing Mdm4 overexpression with and without p73 loss.

Main Results:

  • p73 loss did not rescue Mdm4-deficient embryonic lethality or the runted phenotype in Mdm4(Δ2/Δ2) p53(+/-) embryos.
  • Loss of p73 did not rescue the Mdm4-null brain phenotype in the developing central nervous system.
  • Overexpression of Mdm4 combined with p73 loss did not alter mouse survival or tumor spectrum compared to Mdm4 overexpression alone.

Conclusions:

  • The Mdm4-p73 axis is subordinate to the dominant role of p53 in both development and tumorigenesis.
  • Understanding p53 family member roles may inform cancer treatment strategies.

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