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PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest

Jiyong Liang1, Judit Zubovitz, Teresa Petrocelli

  • 1Molecular and Cell Biology, Sunnybrook and Women's College Health Sciences Centre, St. Mary's Hospital, McGill University, Montreal, Quebec.

Nature Medicine
|September 24, 2002
PubMed

Insights

Protein kinase B (PKB)/Akt activation promotes breast cancer by preventing the nuclear import of p27, a cell cycle inhibitor. This cytoplasmic mislocalization of p27 leads to resistance against growth-inhibitory signals and poor patient prognosis.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Cancer Signaling

Background:

  • Mechanisms linking cytokine signaling and cell cycle regulation in cancer remain unclear.
  • Protein kinase B (PKB)/Akt signaling plays a role in cell growth and survival.

Purpose of the Study:

  • To elucidate the role of PKB/Akt in breast cancer progression.
  • To investigate how PKB/Akt signaling affects the function of the cell cycle inhibitor p27.

Main Methods:

  • Akt transfection and expression studies in cell lines.
  • Analysis of p27 localization and phosphorylation.
  • In vitro nuclear import assays.
  • Correlation of p27 localization with patient survival data.

Main Results:

  • Akt activation led to cytoplasmic accumulation of p27, impairing its nuclear import.
  • Phosphorylation of p27 at threonine 157 by Akt was critical for its cytoplasmic mislocalization.
  • Cells with activated Akt and cytoplasmic p27 showed resistance to G1 arrest.
  • Cytoplasmic p27 in human breast cancers correlated with Akt activation and poor prognosis.

Conclusions:

  • Akt signaling contributes to breast cancer progression by inhibiting p27 nuclear import and function.
  • This mechanism of Akt-mediated p27 cytoplasmic sequestration represents a novel pathway in aggressive breast cancer.
  • Targeting the Akt/p27 interaction may offer therapeutic strategies for breast cancer.

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