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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
09:18

Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death

Published on: December 27, 2016

Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor

A Brunet1, A Bonni, M J Zigmond

  • 1Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.

Cell
|April 2, 1999
PubMed

Insights

Survival factors prevent cell death by regulating the transcription factor FKHRL1. Akt phosphorylation keeps FKHRL1 in the cytoplasm, but its absence triggers nuclear entry and apoptosis.

Area of Science:

  • Cellular biology
  • Molecular biology
  • Biochemistry

Background:

  • Survival factors inhibit apoptosis through Akt activation, phosphorylating BAD and Caspase 9.
  • The serine/threonine kinase Akt plays a crucial role in cell survival pathways.
  • Apoptosis, or programmed cell death, is a tightly regulated cellular process.

Purpose of the Study:

  • To investigate the role of Akt in regulating the Forkhead transcription factor FKHRL1.
  • To elucidate the mechanism by which survival factors influence FKHRL1 activity and localization.
  • To determine FKHRL1's contribution to apoptosis induction.

Main Methods:

  • Western blotting to detect protein phosphorylation.
  • Immunoprecipitation to study protein-protein interactions (Akt, FKHRL1, 14-3-3 proteins).
  • Subcellular fractionation to determine FKHRL1 localization (cytoplasmic vs. nuclear).
  • Quantitative PCR and reporter assays to assess target gene expression.

Main Results:

  • Akt phosphorylates FKHRL1 in the presence of survival factors.
  • Phosphorylated FKHRL1 binds to 14-3-3 proteins and remains in the cytoplasm.
  • Survival factor withdrawal causes FKHRL1 dephosphorylation, nuclear translocation, and activation of target genes.
  • FKHRL1 nuclear translocation is associated with the induction of apoptosis, including Fas ligand expression.

Conclusions:

  • Akt-mediated phosphorylation of FKHRL1 is a key mechanism for survival factor-mediated suppression of apoptosis.
  • FKHRL1 acts as a pro-apoptotic transcription factor upon nuclear translocation.
  • This pathway highlights a novel regulatory axis controlling cell fate decisions.

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