Laforin negatively regulates cell cycle progression through glycogen synthase kinase 3beta-dependent mechanisms.
Glycogen synthase kinase 3beta (GSK-3beta) 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-3beta 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-3beta while having no effect on the phosphorylation of Ser21 on GSK-3alpha. In the GSK-3beta(+/+) but not the GSK-3beta(-/-) 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-3beta 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-3beta and regulates cell cycle progression by GSK-3beta-dependent mechanisms. These data provide a cellular basis for the tumor suppression activity of laforin.
Liu
Runhua
R
Department of Surgery, Division of Immunotherapy, Program of Molecular Mechanism of Diseases andComprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, USA.
Wang
Lizhong
L
Chen
Chong
C
Liu
Yan
Y
Zhou
Penghui
P
Wang
Yin
Y
Wang
Xirui
X
Turnbull
Julie
J
Minassian
Berge A
BA
Liu
Yang
Y
Zheng
Pan
P
D000818:Animals; D002453:Cell Cycle; D002478:Cells, Cultured; D016213:Cyclins / Q000235:genetics; D054637:Dual-Specificity Phosphatases / Q000502:physiology*; D005347:Fibroblasts / Q000166:cytology; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D013950:Thymus Gland / Q000166:cytology; D025521:Tumor Suppressor Proteins / Q000378:metabolism / Q000502:physiology
D016213:Cyclins; D025521:Tumor Suppressor Proteins; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D054637:Dual-Specificity Phosphatases; C491989:Epm2a protein, mouse; D054558:Protein Tyrosine Phosphatases, Non-Receptor