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HER2-Akt signaling in regulating COP9 signalsome subunit 6 and p53

Yuwen Xue1, Jian Chen, Hyun-Ho Choi

  • 1Department of Pulmonary Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China.

Cell Cycle (Georgetown, Tex.)
|October 26, 2012
PubMed

Insights

The Akt pathway, activated in HER2-cancer, elevates COP9 signalosome subunit 6 (CSN6) by preventing its degradation. This leads to decreased p53 levels, promoting cancer growth and DNA damage.

Area of Science:

  • Molecular oncology
  • Cell signaling pathways
  • Cancer biology

Background:

  • HER2/neu oncogene overexpression is common in many cancers.
  • The PI3K-Akt pathway is frequently activated in HER2-overexpressing cancers.
  • COP9 signalosome subunit 6 (CSN6) regulates p53 stability via MDM2, but its upstream control is unknown.

Purpose of the Study:

  • To investigate the link between the HER2-Akt axis and CSN6 regulation.
  • To elucidate the role of Akt in controlling CSN6 expression and stability.
  • To understand the downstream consequences of Akt-mediated CSN6 regulation on p53 and cancer progression.

Main Methods:

  • Investigated Akt's effect on CSN6 expression and stability using ectopic expression and inhibition.
  • Determined the mechanism of Akt-mediated CSN6 regulation, including phosphorylation at Ser 60.
  • Assessed the impact of Akt-CSN6 signaling on p53 degradation, DNA damage, and cellular transformation.

Main Results:

  • Akt acts as a positive regulator of CSN6, increasing its expression and stability.
  • Akt phosphorylates CSN6 at Ser 60, inhibiting its ubiquitin-mediated degradation.
  • Akt-induced CSN6 elevation leads to p53 degradation, enhanced transformation, and increased DNA damage.

Conclusions:

  • Akt is a key positive regulator of CSN6.
  • Activation of Akt in HER2-positive cancers can lead to elevated CSN6, reduced p53, and increased DNA damage, promoting tumor growth.
  • Targeting the Akt-CSN6 axis may offer therapeutic strategies for HER2-overexpressing cancers.

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