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Molecular and Cellular Biology, June 2006, p. 4185-4200, Vol. 26, No. 11
0270-7306/06/$08.00+0     doi:10.1128/MCB.01055-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

N-Cadherin and Keratinocyte Growth Factor Receptor Mediate the Functional Interplay between Ki-RASG12V and p53V143A in Promoting Pancreatic Cell Migration, Invasion, and Tissue Architecture Disruption

Therese B. Deramaudt,1,2 Munenori Takaoka,1,2 Rabi Upadhyay,5 Mark J. Bowser,1,2 Jess Porter,1,2 Amy Lee,1,2 Ben Rhoades,1,2 Cameron N. Johnstone,1,2 Ralph Weissleder,5 Sunil R. Hingorani,2,4 Umar Mahmood,5 and Anil K. Rustgi1,2,3,4*

Gastroenterology Division,1 Department of Medicine,2 Department of Genetics,3 Abramson Family Cancer Center and Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania,4 Center for Molecular Imaging Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts5

Received 7 June 2005/ Returned for modification 10 July 2005/ Accepted 17 March 2006

The genetic basis of pancreatic ductal adenocarcinoma, which constitutes the most common type of pancreatic malignancy, involves the sequential activation of oncogenes and inactivation of tumor suppressor genes. Among the pivotal genetic alterations are Ki-RAS oncogene activation and p53 tumor suppressor gene inactivation. We explain that the combination of these genetic events facilitates pancreatic carcinogenesis as revealed in novel three-dimensional cell (spheroid cyst) culture and in vivo subcutaneous and orthotopic xenotransplantation models. N-cadherin, a member of the classic cadherins important in the regulation of cell-cell adhesion, is induced in the presence of Ki-RAS mutation but subsequently downregulated with the acquisition of p53 mutation as revealed by gene microarrays and corroborated by reverse transcription-PCR and Western blotting. N-cadherin modulates the capacity of pancreatic ductal cells to migrate and invade, in part via complex formation with keratinocyte growth factor receptor and neural cell adhesion molecule and in part via interaction with p120-catenin. However, modulation of these complexes by Ki-RAS and p53 leads to enhanced cell migration and invasion. This preferentially induces the downstream effector AKT over mitogen-activated protein kinase to execute changes in cellular behavior. Thus, we are able to define molecules that in part are directly affected by Ki-RAS and p53 during pancreatic ductal carcinogenesis, and this provides a platform for potential new molecularly based therapeutic interventions.

* Corresponding author. Mailing address: University of Pennsylvania, 415 Curie Boulevard, Philadelphia, PA 19104-2144. Phone: (215) 898-0154. Fax: (215) 573-5412. E-mail: anil2{at}mail.med.upenn.edu.

Molecular and Cellular Biology, June 2006, p. 4185-4200, Vol. 26, No. 11
0270-7306/06/$08.00+0     doi:10.1128/MCB.01055-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Wescott, M. P., Rustgi, A. K. (2008). Pancreatic Cancer: Translating Lessons from Mouse Models and Hereditary Syndromes. Cancer Prevention Research 1: 503-506 [Abstract] [Full Text]  
  • Johnstone, C. N., Mongroo, P. S., Rich, A. S., Schupp, M., Bowser, M. J., deLemos, A. S., Tobias, J. W., Liu, Y., Hannigan, G. E., Rustgi, A. K. (2008). Parvin- Inhibits Breast Cancer Tumorigenicity and Promotes CDK9-Mediated Peroxisome Proliferator-Activated Receptor Gamma 1 Phosphorylation. Mol. Cell. Biol. 28: 687-704 [Abstract] [Full Text]  
  • Deramaudt, T. B., Sachdeva, M. M., Wescott, M. P., Chen, Y., Stoffers, D. A., Rustgi, A. K. (2006). The PDX1 Homeodomain Transcription Factor Negatively Regulates the Pancreatic Ductal Cell-specific Keratin 19 Promoter. J. Biol. Chem. 281: 38385-38395 [Abstract] [Full Text]  
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