FoxM1 promotes β-catenin nuclear localization and controls Wnt target-gene expression and glioma tumorigenesis.
Wnt/β-catenin signaling is essential for stem cell regulation and tumorigenesis, but its molecular mechanisms are not fully understood. Here, we report that FoxM1 is a downstream component of Wnt signaling and is critical for β-catenin transcriptional function in tumor cells. Wnt3a increases the level and nuclear translocation of FoxM1, which binds directly to β-catenin and enhances β-catenin nuclear localization and transcriptional activity. Genetic deletion of FoxM1 in immortalized neural stem cells abolishes β-catenin nuclear localization. FoxM1 mutations that disrupt the FoxM1-β-catenin interaction or FoxM1 nuclear import prevent β-catenin nuclear accumulation in tumor cells. FoxM1-β-catenin interaction controls Wnt target gene expression, is required for glioma formation, and represents a mechanism for canonical Wnt signaling during tumorigenesis.
Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Nu
N
Zhang
Ping
P
Wei
Aihua
A
Gong
Wen-Tai
WT
Chiu
Hsueh-Te
HT
Lee
Howard
H
Colman
He
H
Huang
Jianfei
J
Xue
Mingguang
M
Liu
Yong
Y
Wang
Raymond
R
Sawaya
Keping
K
Xie
W K Alfred
WK
Yung
René H
RH
Medema
Xi
X
He
Suyun
S
Huang
D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism* / Q000502:physiology; D051176:beta Catenin / Q000032:analysis / Q000378:metabolism*
C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C491524:Foxm1 protein, mouse; D051153:Wnt Proteins; D051176:beta Catenin