PUBLICATION
MEKK2 and MEKK3 suppress Hedgehog pathway-dependent medulloblastoma by inhibiting GLI1 function
- Authors
- Lu, J., Liu, L., Zheng, M., Li, X., Wu, A., Wu, Q., Liao, C., Zou, J., Song, H.
- ID
- ZDB-PUB-190227-25
- Date
- 2018
- Source
- Oncogene 37: 3864-3878 (Journal)
- Registered Authors
- Zou, Jian
- Keywords
- none
- MeSH Terms
-
- Animals
- Cell Line
- Cell Proliferation/physiology
- Fibroblast Growth Factor 2/metabolism
- HEK293 Cells
- Hedgehog Proteins/metabolism*
- Humans
- MAP Kinase Kinase Kinase 3/metabolism*
- MAP Kinase Kinase Kinases/metabolism*
- Male
- Medulloblastoma/metabolism*
- Mice
- Mice, Nude
- NIH 3T3 Cells
- Phosphorylation/physiology
- Repressor Proteins/metabolism
- Signal Transduction/physiology
- Transcription Factors/metabolism
- Transcription, Genetic/physiology
- Zebrafish
- Zinc Finger Protein GLI1/metabolism*
- PubMed
- 29662197 Full text @ Oncogene
Citation
Lu, J., Liu, L., Zheng, M., Li, X., Wu, A., Wu, Q., Liao, C., Zou, J., Song, H. (2018) MEKK2 and MEKK3 suppress Hedgehog pathway-dependent medulloblastoma by inhibiting GLI1 function. Oncogene. 37:3864-3878.
Abstract
Hedgehog (Hh) pathway plays a pivotal role in diverse aspects of development and postnatal physiology. Perturbation of Hh signaling and activation of GLI1 (glioma-associated oncogene 1), a dedicated transcription factor for Hh pathway, are highly associated with several cancers, such as medulloblastoma and basal cell carcinoma. Dynamic and precise control of GLI1 activity is thus important to ensure proper homeostasis and tumorigenesis. Here we show that MEKK2 (MAP3K2) and MEKK3 (MAP3K3) inhibit GLI1 transcriptional activity and oncogenic function through phosphorylation on multiple Ser/Thr sites of GLI1, which reduces GLI1 protein stability, DNA-binding ability, and increases the association of GLI1 with SUFU. Interestingly, MEKK2 and MEKK3 are responsible for FGF2-mediated inhibition on Hh signaling. Moreover, expression of MEKK2 and MEKK3 inhibits medulloblastoma cell proliferation and negatively correlates with Hh pathway activity in medulloblastoma clinical samples. Together, these findings reveal a novel noncanonical GLI1 regulation and provide a potential therapeutic target for the treatment of cancers with aberrant Hh pathway activation, such as medulloblastoma.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping