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Yeast As a Chassis for Developing Functional Assays to Study Human P53
14:57

Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling

Andrei V Budanov1, Michael Karin

  • 1Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, MC0723, La Jolla, CA 92093, USA.

Cell
|August 12, 2008
PubMed

Insights

The tumor suppressor p53, activated by stress, uses Sestrins to inhibit mTOR signaling. This research clarifies how p53 controls cell growth via the AMPK-TSC2-mTOR pathway, revealing a crucial link for cancer research.

Area of Science:

  • Molecular Biology
  • Cellular Signaling
  • Oncology

Background:

  • The tumor suppressor p53 regulates cell proliferation and growth in response to stress.
  • Mammalian target of rapamycin (mTOR) positively regulates cell growth and is inhibited by the TSC1:TSC2 complex.
  • The precise mechanism linking p53-mediated genotoxic stress response to mTOR inhibition was previously unclear.

Purpose of the Study:

  • To elucidate the mechanism by which p53-activated genes link genotoxic stress to mTOR signaling inhibition.
  • To investigate the role of Sestrin1 and Sestrin2 in this pathway.

Main Methods:

  • Analysis of p53 target genes Sestrin1 and Sestrin2.
  • Investigation of AMP-responsive protein kinase (AMPK) activation and its downstream effects.
  • Assessment of TSC2 phosphorylation and GTPase-activating protein (GAP) activity.
  • Utilizing Sestrin2-deficient mice to study mTOR signaling in vivo.

Main Results:

  • Sestrin1 and Sestrin2 activate AMPK.
  • Activated AMPK phosphorylates TSC2, enhancing its GAP activity and inhibiting mTOR.
  • Sestrin2-deficient mice exhibit impaired mTOR inhibition following genotoxic stress.
  • Sestrin1 and Sestrin2 establish a link between p53, genotoxic stress, and mTOR signaling.

Conclusions:

  • Sestrin1 and Sestrin2 are key mediators linking p53 activation during genotoxic stress to the inhibition of mTOR signaling.
  • This pathway represents a critical mechanism for controlling cell proliferation and growth under stress conditions.
  • Understanding this link has implications for developing novel cancer therapies targeting cell growth pathways.

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