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<scp>TGIF</scp> 1 functions as a tumor suppressor in pancreatic ductal adenocarcinoma
- Source :
- EMBO Journal, EMBO Journal, EMBO Press, 2019, 38 (13), ⟨10.15252/embj.2018101067⟩, EMBO J
- Publication Year :
- 2019
- Publisher :
- EMBO, 2019.
-
Abstract
- A prominent function of TGIF1 is suppression of transforming growth factor beta (TGF‐β) signaling, whose inactivation is deemed instrumental to the progression of pancreatic ductal adenocarcinoma (PDAC), as exemplified by the frequent loss of the tumor suppressor gene SMAD4 in this malignancy. Surprisingly, we found that genetic inactivation of Tgif1 in the context of oncogenic Kras, Kras(G12D), culminated in the development of highly aggressive and metastatic PDAC despite de‐repressing TGF‐β signaling. Mechanistic experiments show that TGIF1 associates with Twist1 and inhibits Twist1 expression and activity, and this function is suppressed in the vast majority of human PDACs by Kras(G12D)/MAPK‐mediated TGIF1 phosphorylation. Ablating Twist1 in Kras (G12D) ;Tgif1 (KO) mice completely blunted PDAC formation, providing the proof‐of‐principle that TGIF1 restrains Kras(G12D)‐driven PDAC through its ability to antagonize Twist1. Collectively, these findings pinpoint TGIF1 as a potential tumor suppressor in PDAC and further suggest that sustained activation of TGF‐β signaling might act to accelerate PDAC progression rather than to suppress its initiation.
- Subjects :
- animal structures
endocrine system diseases
Tumor suppressor gene
Context (language use)
medicine.disease_cause
Malignancy
General Biochemistry, Genetics and Molecular Biology
law.invention
Proto-Oncogene Proteins p21(ras)
Mice
03 medical and health sciences
0302 clinical medicine
Transforming Growth Factor beta
law
Cell Line, Tumor
medicine
Animals
Humans
[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology
Neoplasm Metastasis
Molecular Biology
ComputingMilieux_MISCELLANEOUS
030304 developmental biology
Homeodomain Proteins
0303 health sciences
General Immunology and Microbiology
biology
General Neuroscience
Twist-Related Protein 1
Nuclear Proteins
Articles
Transforming growth factor beta
medicine.disease
digestive system diseases
Gene Expression Regulation, Neoplastic
Pancreatic Neoplasms
Repressor Proteins
Disease Models, Animal
Disease Progression
biology.protein
Cancer research
Phosphorylation
Suppressor
KRAS
030217 neurology & neurosurgery
Carcinoma, Pancreatic Ductal
Signal Transduction
Transforming growth factor
Subjects
Details
- ISSN :
- 14602075 and 02614189
- Volume :
- 38
- Database :
- OpenAIRE
- Journal :
- The EMBO Journal
- Accession number :
- edsair.doi.dedup.....2d119f5326b9e023ffc1043e4466ef9d