GSK3 beta mediates suppression of cyclin D2 expression by tumor suppressor PTEN.
PTEN, encoding a lipid phosphatase, is a tumor suppressor gene and is mutated in various types of cancers. It is reported to regulate G1 to S phase transition of the cell cycle by influencing the expression, protein stability and subcellular location of cyclin D1. Here, we provide evidence that PTEN modulates the transcription and protein stability of cyclin D2. Targeted deletion of Pten in mouse embryonic fibroblasts (MEFs) endowed cells with greater potential to overcome G1 arrest than wild-type MEFs and led to the elevated expression of cyclin D2, which was suppressed by the introduction of PTEN. We further defined a pathway involving GSK3beta and beta-catenin/TCF in PTEN-mediated suppression of cyclin D2 transcription. LiCl, an inhibitor of GSK3beta, abolished inhibitory effect of PTEN on cyclin D2 expression, and TCF members could directly bind to the promoter of cyclin D2 and regulate its transcription in a CREB-dependent manner. Our results indicate that the downregulation of cyclin D2 expression by PTEN is mediated by the GSK3beta/beta-catenin/TCF pathway in cooperation with CREB, and suggest a convergence from the PI-3 kinase/PTEN pathway and the Wnt pathway in modulation of cyclin D2 expression.
Huang
W
W
Department of Biological Sciences and Biotechnology, State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua University, Beijing, China.
Chang
H Y
HY
Fei
T
T
Wu
H
H
Chen
Y-G
YG
D000818:Animals; D001483:Base Sequence; D056742:Cyclin D2; D016213:Cyclins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D015536:Down-Regulation / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D006367:HeLa Cells; D006801:Humans; D008546:Melanoma, Experimental / Q000201:enzymology / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D051059:PTEN Phosphohydrolase / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
C080336:CCND2 protein, human; C486196:Ccnd2 protein, mouse; D056742:Cyclin D2; D016213:Cyclins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D051059:PTEN Phosphohydrolase