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Purification of Ubiquitinated p53 Proteins from Mammalian Cells
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The Spatiotemporal Pattern and Intensity of p53 Activation Dictates Phenotypic Diversity in p53-Driven Developmental

Margot E Bowen1, Jacob McClendon1, Hannah K Long2

  • 1Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA.

Developmental Cell
|June 11, 2019
PubMed

Insights

The p53 transcription factor

Area of Science:

  • Developmental Biology
  • Molecular Biology
  • Genetics

Background:

  • Inappropriate activation of the p53 transcription factor is linked to various developmental syndromes.
  • The precise mechanisms by which p53 influences specific syndrome phenotypes are not fully understood.

Purpose of the Study:

  • To investigate how spatial expression, temporal profile, and magnitude of p53 activation during embryogenesis contribute to distinct developmental phenotypes.
  • To elucidate the cellular and molecular basis of p53-driven developmental syndromes.

Main Methods:

  • Utilized diverse mouse strains to precisely control p53 activation patterns during embryonic development.
  • Analyzed phenotypes resulting from p53 hyperactivation in specific embryonic tissues, including neural crest, facial ectoderm, anterior heart field, and endothelium.
  • Investigated cellular responses (cell-cycle arrest, apoptosis) and gene expression programs associated with p53 activation.

Main Results:

  • Distinct developmental phenotypes arise from p53 activation in specific embryonic tissues (neural crest, facial ectoderm, heart, endothelium).
  • The timing and level of p53 hyperactivation significantly impact the resulting phenotypic outcomes.
  • Cellular responses to p53 are cell-type dependent, involving either cell-cycle arrest or apoptosis, with gene expression programs being key determinants.

Conclusions:

  • The spatial and temporal dynamics of p53 activation are critical determinants of specific developmental syndrome phenotypes.
  • Gene expression programs, rather than mitochondrial status, primarily dictate the cellular response to p53.
  • This study provides a framework for understanding p53's role in mediating diverse developmental disorders.
Keywords:
Mdm2apoptosiscardiovascularcongenital defectcraniofacialdevelopmentembryoneural crestp53syndrome

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