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Heterozygous loss of TSC2 alters p53 signaling and human stem cell reprogramming

Laura C Armstrong1, Grant Westlake1, John P Snow1

  • 1Division of Pediatric Neurology, Department of Pediatrics, Vanderbilt University Medical Center, D4105 Medical Center North, Nashville, TN 37232, USA.

Human Molecular Genetics
|October 4, 2017
PubMed

Insights

Tuberous sclerosis complex (TSC) involves gene mutations affecting cell growth. This study found that TSC2 gene variations increase p53 levels, impacting stem cell reprogramming and TSC development.

Area of Science:

  • Genetics
  • Developmental Biology
  • Cell Biology

Background:

  • Tuberous sclerosis complex (TSC) is a pediatric genetic disorder characterized by abnormal cell growth and differentiation.
  • TSC results from loss-of-function mutations in TSC1 or TSC2 genes, which are critical regulators of mTOR kinase activity.
  • Understanding early developmental aberrations in TSC is crucial for therapeutic strategies.

Purpose of the Study:

  • To investigate the role of TSC2 and p53 interactions in the pathogenesis of Tuberous Sclerosis Complex.
  • To analyze stem cell reprogramming efficiency in TSC patient-derived cells.
  • To determine the impact of TSC2 gene dosage on p53 levels and cellular reprogramming.

Main Methods:

  • Generation of induced pluripotent stem cells (iPSCs) from dermal fibroblasts of TSC patients.
  • Assessment of reprogramming plasmid integration rates in TSC-derived stem cells.
  • Quantification of p53 protein levels in human fibroblasts and stem cells with varying TSC2 genotypes (heterozygous and homozygous mutants).

Main Results:

  • Stem cells derived from TSC patients exhibited a high rate of reprogramming plasmid integration, including shRNA targeting TP53.
  • Loss of a single TSC2 allele in human fibroblasts was sufficient to elevate p53 levels and hinder stem cell reprogramming.
  • Elevated p53 levels were consistently observed in TSC2 heterozygous and homozygous mutant human stem cells, indicating conserved TSC2-p53 interactions.

Conclusions:

  • TSC2 heterozygous and homozygous mutant cells significantly contribute to the pathogenesis of Tuberous Sclerosis Complex.
  • The p53 pathway plays a critical role during the stem cell reprogramming process in the context of TSC.
  • The interaction between TSC2 and p53 is consistent across different cell types and gene dosage, highlighting its importance in TSC.

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