Impaired JNK signaling cooperates with KrasG12D expression to accelerate pancreatic ductal adenocarcinoma

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

URL: http://www.ncbi.nlm.nih.gov/pubmed/24713432
DOI: 10.1158/0008-5472

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: http://repository.cshl.edu/id/eprint/30538

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