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Purification of Ubiquitinated p53 Proteins from Mammalian Cells
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A p53-phosphoinositide signalosome regulates nuclear AKT activation

Mo Chen1, Suyong Choi1, Tianmu Wen1

  • 1University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI, USA.

Nature Cell Biology
|July 7, 2022
PubMed

Insights

Genotoxic stress activates nuclear AKT via a p53-dependent pathway, distinct from the membrane-associated PI3K-AKT pathway. This novel mechanism regulates apoptosis and offers therapeutic potential.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Cancer Signaling

Background:

  • The tumor suppressor p53 and the PI3K-AKT pathway are crucial for cell growth and apoptosis, frequently altered in cancer.
  • Canonical PI3K-AKT signaling occurs at the cell membrane.

Purpose of the Study:

  • To elucidate a novel mechanism of nuclear AKT activation.
  • To investigate the role of p53 in regulating AKT activity following genotoxic stress.

Main Methods:

  • Investigated p53-dependent nuclear AKT activation using genotoxic stress models.
  • Analyzed the formation of p53-phosphoinositide complexes in the nucleoplasm.
  • Assessed the impact of this pathway on DNA damage-induced apoptosis and FOXO phosphorylation.

Main Results:

  • Genotoxic stress triggers nuclear PI3K to form a p53-PtdIns(3,4,5)P3 complex, activating nuclear AKT and inhibiting apoptosis.
  • Wild-type p53 mediates an on/off nuclear AKT activation, while mutant p53 promotes high basal activity.
  • PTEN dephosphorylates the complex, inhibiting AKT activation; this pathway is insensitive to current PI3K inhibitors.

Conclusions:

  • A novel p53-phosphoinositide signalosome activates nuclear AKT independently of the membrane-localized PI3K-AKT pathway.
  • This distinct nuclear pathway plays a critical role in regulating apoptosis following genotoxic stress.
  • The pathway's insensitivity to clinical PI3K inhibitors highlights its potential as a therapeutic target in cancer.

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