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GSK3 beta mediates suppression of cyclin D2 expression by tumor suppressor PTEN

W Huang1, H Y Chang, T Fei

  • 1Department of Biological Sciences and Biotechnology, State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua University, Beijing, China.

Oncogene
|October 18, 2006
PubMed

Insights

The tumor suppressor PTEN regulates cyclin D2 expression by inhibiting its transcription via the GSK3beta/beta-catenin/TCF pathway. This finding reveals a link between the PI-3 kinase/PTEN and Wnt signaling pathways in cell cycle control.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Cell Cycle Regulation

Background:

  • PTEN is a crucial tumor suppressor gene frequently mutated in cancers.
  • PTEN influences cell cycle progression, notably the G1 to S phase transition.
  • PTEN's role in regulating cyclin D1 expression and stability is established.

Purpose of the Study:

  • To investigate the role of PTEN in modulating cyclin D2 expression and stability.
  • To elucidate the molecular pathways involved in PTEN-mediated regulation of cyclin D2.
  • To explore the interplay between PTEN signaling and cell cycle control involving cyclin D2.

Main Methods:

  • Utilized mouse embryonic fibroblasts (MEFs) with targeted deletion of Pten.
  • Assessed cyclin D2 expression levels in response to PTEN manipulation.
  • Investigated the involvement of GSK3beta, beta-catenin/TCF, and CREB in PTEN's regulatory mechanism.

Main Results:

  • Pten deletion in MEFs enhanced G1 arrest escape and elevated cyclin D2 expression.
  • PTEN introduction suppressed cyclin D2 expression, confirming its inhibitory role.
  • The GSK3beta/beta-catenin/TCF pathway, modulated by LiCl, was identified as key in PTEN-mediated cyclin D2 suppression.
  • TCF members directly bind to the cyclin D2 promoter in a CREB-dependent manner.

Conclusions:

  • PTEN downregulates cyclin D2 transcription through the GSK3beta/beta-catenin/TCF pathway in conjunction with CREB.
  • This study highlights a convergence of the PI-3 kinase/PTEN pathway and the Wnt pathway in regulating cyclin D2.
  • PTEN's modulation of cyclin D2 offers new insights into its tumor suppressor functions and cell cycle control mechanisms.

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