Davies, C. C., Harvey, E., McMahon, R. F. T., Finegan, K. G., Connor, F., Davis, R. J., Tuveson, D. A., Tournier, C. (April 2014) Impaired JNK signaling cooperates with KrasG12D expression to accelerate pancreatic ductal adenocarcinoma. Cancer Research, 74 (12). pp. 3344-3356. ISSN 15387445
Abstract
The c-Jun N-terminal protein kinase (JNK) and its two direct activators, namely the mitogen-activated protein kinase (MAPK) kinase 4 (MKK4) and MKK7, constitute a signaling node frequently mutated in human pancreatic ductal adenocarcinoma (PDAC). Here we demonstrate the cooperative interaction of endogenous expression of KrasG12D with loss-of-function mutations in mkk4 or both, mkk4 and mkk7 genes in the pancreas. More specifically, impaired JNK signaling in a subpopulation of Pdx1-expressing cells dramatically accelerated the appearance of KrasG12D-induced acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasias, which rapidly progressed to invasive PDAC within 10 weeks of age. Furthermore, inactivation of mkk4/ mkk7 compromised acinar regeneration following acute inflammatory stress by locking damaged exocrine cells in a permanently de-differentiated state. Therefore, we propose that JNK signaling exerts its tumor suppressive function in the pancreas by antagonizing the metaplastic conversion of acinar cells toward a ductal fate capable of responding to oncogenic stimulation. ©2014 AACR.
| Item Type: | Paper |
|---|---|
| Subjects: | bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase diseases & disorders > cancer > cancer types > pancreatic cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types organs, tissues, organelles, cell types and functions > tissues types and functions > signal transduction |
| CSHL Authors: | |
| Communities: | CSHL labs > Tuveson lab |
| Depositing User: | Matt Covey |
| Date: | 8 April 2014 |
| Date Deposited: | 18 Jul 2014 15:12 |
| Last Modified: | 18 Jul 2014 15:12 |
| PMCID: | PMC4058314 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/30538 |
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