14-3-3β regulates the proliferation of glioma cells through the GSK3β/β-catenin signaling pathway.
We previously demonstrated that 14-3-3β is overexpressed in astrocytomas; however, the underlying mechanisms are poorly understood. Based on the reported multiple functions of 14-3-3β, we hypothesized that it interacts with glycogen synthase kinase 3 β (GSK3β), which regulates β-catenin-mediated oncogene expression and contributes to tumorigenesis and astrocytoma progression. To test these hypotheses, we used 14-3-3β overexpression vectors and small interfering RNA (siRNA) transfection in the human normal astrocyte cell line SVGp12 and the glioma cell line U87, respectively. The results showed that overexpression of 14-3-3β promoted the proliferation of SVGp12 cells, while knockdown of 14-3-3β inhibited the proliferation of U87 cells as analyzed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and bromodeoxyuridine (BrdU) assays. In Flag-tagged 14-3-3β-overexpressing cells, GSK3β was co-immunoprecipitated with 14-3-3β using a Flag antibody. Knockdown of β-catenin by siRNA blocked cell proliferation induced by overexpression of 14-3-3β. Furthermore, overexpression of 14-3-3β suppressed the phosphorylation of β-catenin leading to its accumulation and nuclear translocation as revealed by western blot analysis. In addition, β-catenin nuclear translocation induced by overexpression of 14-3-3β activated the transcription of oncogenes including c-myc and cyclin D1. Collectively, these results revealed that 14-3-3β regulates the proliferation of astrocytes and glioma cells through the GSK3β/β-catenin signaling pathway. The delineated mechanism of 14-3-3β may be responsible for the tumorigenesis and progression of human astrocytomas. Thus, new therapeutic strategies or drugs aimed at 14-3-3β may have potential for the treatment of human astrocytomas.
Department of Neurosurgery, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou 510010, P.R. China.
Fanghe
F
Gong
Guoliang
G
Wang
Jing
J
Ye
Tiandong
T
Li
Hongmin
H
Bai
Weimin
W
Wang
D048948:14-3-3 Proteins / Q000235:genetics* / Q000378:metabolism; D001254:Astrocytoma / Q000235:genetics* / Q000473:pathology; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000235:genetics* / Q000473:pathology; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D015398:Signal Transduction / Q000235:genetics; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
D048948:14-3-3 Proteins; D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3