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

Runhua Liu, Lizhong Wang, Chong Chen, Yan Liu, Penghui Zhou, Yin Wang, Xirui Wang, Julie Turnbull, Berge A. Minassian, Yang Liu, Pan Zheng

Research output: Contribution to journalArticle

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Abstract

Glycogen synthase kinase 3β (GSK-3β) represses cell cycle progression by directly phosphorylating cyclin D1 and indirectly regulating cyclin D1 transcription by inhibiting Wnt signaling. Recently, we reported that the Epm2a-encoded laforin is a GSK-3β phosphatase and a tumor suppressor. The cellular mechanism for its tumor suppression remains unknown. Using ex vivo thymocytes and primary embryonic fibroblasts from Epm2a-/- mice, we show here a general function of laforin in the cell cycle regulation and repression of cyclin D1 expression. Moreover, targeted mutation of Epm2a increased the phosphorylation of Ser9 on GSK-3β while having no effect on the phosphorylation of Ser21 on GSK-3α. In the GSK-3β+/+ but not the GSK-3β-/- cells, Epm2a small interfering RNA significantly enhanced cell growth. Consistent with an increased level of cyclin D1, the phosphorylation of retinoblastoma protein (Rb) and the levels of Rb-E2F-regulated genes cyclin A, cyclin E, MCM3, and PCNA are also elevated. Inhibitors of GSK-3β selectively increased the cell growth of Epm2a +/+ but not of Epm2a-/- cells. Taken together, our data demonstrate that laforin is a selective phosphatase for GSK-3β and regulates cell cycle progression by GSK-3β-dependent mechanisms. These data provide a cellular basis for the tumor suppression activity of laforin.

Original languageEnglish (US)
Pages (from-to)7236-7244
Number of pages9
JournalMolecular and Cellular Biology
Volume28
Issue number23
DOIs
StatePublished - Dec 1 2008

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Glycogen Synthase Kinase 3
Cell Cycle
Cyclin D1
Phosphorylation
Phosphoric Monoester Hydrolases
Cyclin A
Cyclin E
Neoplasms
Retinoblastoma Protein
Proliferating Cell Nuclear Antigen
Thymocytes
Growth
Small Interfering RNA
Fibroblasts
Mutation

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Laforin negatively regulates cell cycle progression through glycogen synthase kinase 3β-dependent mechanisms. / Liu, Runhua; Wang, Lizhong; Chen, Chong; Liu, Yan; Zhou, Penghui; Wang, Yin; Wang, Xirui; Turnbull, Julie; Minassian, Berge A.; Liu, Yang; Zheng, Pan.

In: Molecular and Cellular Biology, Vol. 28, No. 23, 01.12.2008, p. 7236-7244.

Research output: Contribution to journalArticle

Liu, R, Wang, L, Chen, C, Liu, Y, Zhou, P, Wang, Y, Wang, X, Turnbull, J, Minassian, BA, Liu, Y & Zheng, P 2008, 'Laforin negatively regulates cell cycle progression through glycogen synthase kinase 3β-dependent mechanisms', Molecular and Cellular Biology, vol. 28, no. 23, pp. 7236-7244. https://doi.org/10.1128/MCB.01334-08
Liu, Runhua ; Wang, Lizhong ; Chen, Chong ; Liu, Yan ; Zhou, Penghui ; Wang, Yin ; Wang, Xirui ; Turnbull, Julie ; Minassian, Berge A. ; Liu, Yang ; Zheng, Pan. / Laforin negatively regulates cell cycle progression through glycogen synthase kinase 3β-dependent mechanisms. In: Molecular and Cellular Biology. 2008 ; Vol. 28, No. 23. pp. 7236-7244.
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