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PKB/AKT phosphorylation of the transcription factor Twist-1 at Ser42 inhibits p53 activity in response to DNA damage

A Vichalkovski1, E Gresko, D Hess

  • 1Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, Basel, Switzerland.

Oncogene
|April 20, 2010
PubMed

Insights

Protein kinase B (PKB/Akt) promotes cancer cell survival by phosphorylating Twist-1, inhibiting p53

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • Protein kinase B (PKB/Akt) is crucial for cell survival and is often upregulated in cancers.
  • PKB/Akt regulates various cellular processes through phosphorylation of target proteins.
  • The anti-apoptotic protein Twist-1 plays a role in cancer progression.

Purpose of the Study:

  • To investigate the role of PKB/Akt in regulating the anti-apoptotic protein Twist-1.
  • To determine the functional consequences of PKB/Akt-mediated phosphorylation of Twist-1.
  • To explore the implications of this interaction in cancer development.

Main Methods:

  • In vitro phosphorylation assays to identify PKB/Akt targets.
  • Cellular studies using wild-type and mutant Twist-1.
  • DNA damage induction using gamma-irradiation and adriamycin.
  • Analysis of p53, p21(Waf1), and Bax expression.
  • In vivo studies in human cancer tissues.

Main Results:

  • PKB/Akt directly phosphorylates the anti-apoptotic protein Twist-1 at Serine 42.
  • Phosphorylation of Twist-1 by PKB/Akt impairs p53 upregulation following DNA damage.
  • This leads to reduced activation of p53 target genes, aberrant cell-cycle regulation, and inhibition of apoptosis.
  • A Twist-1 S42A mutant failed to confer resistance to DNA damage, confirming PKB/Akt-dependent phosphorylation's role.
  • Phosphorylation of Twist-1 at Ser42 was observed in human cancer tissues.

Conclusions:

  • PKB/Akt-mediated phosphorylation of Twist-1 at Ser42 is a key mechanism for promoting cancer cell survival.
  • This post-translational modification inhibits the p53 tumor suppressor pathway, contributing to carcinogenesis.
  • Targeting the PKB/Akt-Twist-1 interaction may offer therapeutic strategies for cancer treatment.

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