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Dysregulation of the mTOR pathway in p53-deficient mice

Olga V Leontieva1, Liliya R Novototskaya1, Geraldine M Paszkiewicz1

  • 1Department of Cell Stress Biology; Roswell Park Cancer Institute; Buffalo, NY USA.

Cancer Biology & Therapy
|November 5, 2013
PubMed

Insights

The absence of p53 increases mechanistic target of rapamycin (mTOR) activity in some tissues, potentially promoting cancer. This suggests p53 deficiency creates an environment favorable for tumor development.

Area of Science:

  • Molecular Biology
  • Oncology
  • Aging Research

Background:

  • Mammalian or mechanistic target of rapamycin (mTOR) pathway regulates growth, aging, and cancer.
  • p53 protein interacts extensively with the mTOR pathway, inhibiting it in a cell-dependent manner.
  • p53 deficiency in mice leads to inflammation and cancer.

Purpose of the Study:

  • To investigate the relationship between p53 deficiency and mTOR activity in vivo.
  • To determine the impact of p53 loss on insulin and IGF-1 signaling.
  • To explore how radiation affects these pathways in the context of p53 status.

Main Methods:

  • Analysis of phosphorylated S6 (p-S6), a marker of mTOR activity, in hearts and livers of p53-deficient (p53(-/-)) and wild-type (p53(+/+)) mice.
  • Measurement of body weight, insulin, and IGF-1 levels.
  • Assessment of Thr-308 Akt phosphorylation following radiation exposure.

Main Results:

  • Increased cardiac p-S6 levels were observed in p53(-/-) mice, correlating with body weight.
  • p53(-/-) mice exhibited mild hyperinsulinemia and a trend towards elevated IGF-1, exacerbated by radiation.
  • Radiation induced Akt phosphorylation in the liver but decreased p-S6 in normal mice, indicating tissue-specific effects and p53's inhibitory role on mTOR.

Conclusions:

  • The absence of p53 leads to increased mTOR activity in specific tissues, potentially contributing to an oncogenic microenvironment.
  • Elevated insulin and IGF-1 levels in p53-deficient mice may further support cancer development.
  • These findings highlight a critical role for p53 in regulating metabolic and growth pathways relevant to cancer and aging.
Keywords:
agingcancerinflammationmTORp53rapalograpamycinsenescence

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