This Article Full Text Full Text (PDF) Supplemental material Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Liu, R. Articles by Zheng, P. Search for Related Content PubMed PubMed Citation Articles by Liu, R. Articles by Zheng, P.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, December 2008, p. 7236-7244, Vol. 28, No. 23
0270-7306/08/$08.00+0     doi:10.1128/MCB.01334-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Laforin Negatively Regulates Cell Cycle Progression through Glycogen Synthase Kinase 3β-Dependent Mechanisms ^,

Runhua Liu,¹ Lizhong Wang,¹ Chong Chen,¹ Yan Liu,¹ Penghui Zhou,¹ Yin Wang,¹ Xirui Wang,¹ Julie Turnbull,⁴ Berge A. Minassian,⁴ Yang Liu,^1,2 and Pan Zheng^1,3*

Division of Immunotherapy, Department of Surgery, Program of Molecular Mechanism of Diseases and Comprehensive Cancer Center,¹ Division of Molecular Medicine and Genetics, Department of Internal Medicine,² Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109,³ Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada⁴

Received 21 August 2008/ Accepted 19 September 2008

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-3. 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.

---

* Corresponding author. Mailing address: Department of Surgery, 1810 BSRB, 109 Zina Pitcher Place, University of Michigan, Ann Arbor, MI 48109. Phone: (734) 615-3464. Fax: (734) 763-2162. E-mail: panz{at}umich.edu

Published ahead of print on 29 September 2008.

Supplemental material for this article may be found at http://mcb.asm.org/.

---

Molecular and Cellular Biology, December 2008, p. 7236-7244, Vol. 28, No. 23
0270-7306/08/$08.00+0     doi:10.1128/MCB.01334-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

This article has been cited by other articles:

• Liu, Y., Wang, Y., Wu, C., Liu, Y., Zheng, P. (2009). Deletions and missense mutations of EPM2A exacerbate unfolded protein response and apoptosis of neuronal cells induced by endoplasm reticulum stress. Hum Mol Genet 18: 2622-2631 [Abstract] [Full Text]  
• Kotting, O., Santelia, D., Edner, C., Eicke, S., Marthaler, T., Gentry, M. S., Comparot-Moss, S., Chen, J., Smith, A. M., Steup, M., Ritte, G., Zeeman, S. C. (2009). STARCH-EXCESS4 Is a Laforin-Like Phosphoglucan Phosphatase Required for Starch Degradation in Arabidopsis thaliana. Plant Cell 21: 334-346 [Abstract] [Full Text]