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Laforin negatively regulates cell cycle progression through glycogen synthase kinase 3beta-dependent mechanisms

Runhua Liu1, Lizhong Wang, Chong Chen

  • 1Department of Surgery, Division of Immunotherapy, Program of Molecular Mechanism of Diseases andComprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, USA.

Molecular and Cellular Biology
|October 1, 2008
PubMed

Insights

Laforin, a phosphatase for Glycogen synthase kinase 3beta (GSK-3beta), suppresses tumor growth by regulating cell cycle progression and cyclin D1 expression through GSK-3beta-dependent mechanisms.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Glycogen synthase kinase 3beta (GSK-3beta) inhibits cell cycle progression by phosphorylating cyclin D1 and Wnt signaling.
  • Laforin, encoded by Epm2a, is a GSK-3beta phosphatase and a known tumor suppressor.
  • The precise cellular mechanism underlying laforin's tumor suppressive activity is not fully understood.

Purpose of the Study:

  • To elucidate the cellular mechanism of laforin's tumor suppression.
  • To investigate laforin's role in cell cycle regulation and cyclin D1 expression.
  • To determine if laforin acts as a selective phosphatase for GSK-3beta.

Main Methods:

  • Utilized ex vivo thymocytes and primary embryonic fibroblasts from Epm2a(-/-) mice.
  • Employed small interfering RNA (siRNA) against Epm2a in GSK-3beta(+/+) and GSK-3beta(-/-) cells.
  • Administered GSK-3beta inhibitors to Epm2a(+/+) and Epm2a(-/-) cells.

Main Results:

  • Laforin deficiency in mice led to increased GSK-3beta phosphorylation at Ser9, without affecting GSK-3alpha.
  • Epm2a knockdown in GSK-3beta(+/+) cells enhanced cell growth and increased cyclin D1, phosphorylated retinoblastoma protein (Rb), and Rb-E2F-regulated genes.
  • GSK-3beta inhibitors selectively promoted the growth of Epm2a(+/+) cells, but not Epm2a(-/-) cells.

Conclusions:

  • Laforin functions as a selective phosphatase for GSK-3beta.
  • Laforin regulates cell cycle progression via GSK-3beta-dependent pathways.
  • These findings provide a cellular basis for laforin's tumor suppressor activity.

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