CG&D
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cell Growth & Differentiation

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Montesano, R.
Right arrow Articles by Schramek, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Montesano, R.
Right arrow Articles by Schramek, H.
Cell Growth & Differentiation Vol. 10, 317-332, May 1999
© 1999 American Association for Cancer Research

Constitutively Active Mitogen-activated Protein Kinase Kinase MEK1 Disrupts Morphogenesis and Induces an Invasive Phenotype in Madin-Darby Canine Kidney Epithelial Cells1

Roberto Montesano2, Jesus V. Soriano, Ghamartaj Hosseini, Michael S. Pepper and Herbert Schramek

Department of Morphology, University Medical Center, CH-1211 Geneva 4, Switzerland [R. M., J. V. S., G. H., M. S. P.], and Department of Physiology, University of Innsbruck, A-6020 Innsbruck, Austria [H. S.]

During certain developmental processes, as well as during tumor progression, polarized epithelial cells integrated within multicellular structures convert into scattered, freely migrating fibroblast-like cells. Despite the biological and clinical importance of this phenomenon, the intracellular biochemical cascades that control the switch between the epithelial and mesenchymal phenotypes have not been elucidated. Using Madin-Darby canine kidney (MDCK) cells (clone C7) as a model system, we have assessed the potential role of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) cascade in the modulation of epithelial plasticity. When grown in three-dimensional collagen gels, MDCK-C7 cells form spherical cysts composed of polarized epithelial cells circumscribing a central lumen. This morphogenetic behavior is profoundly subverted in MDCK-C7 cells expressing a constitutively active MAPK/ERK kinase 1 (caMEK1) mutant (C7-caMEK1 cells). When suspended in collagen gels, C7-caMEK1 cells assume an elongated fibroblastoid shape and are unable to generate multicellular cysts. In addition, when seeded onto the surface of a collagen gel, C7-caMEK1 cells penetrate extensively into the underlying matrix, unlike wild-type and mock-transfected MDCK-C7 cells, which remain confined to the surface of the gel. Similar changes in morphogenetic and invasive properties are observed in MDCK-C7F cells, a nontransfected, stably dedifferentiated derivative of MDCK-C7 cells that expresses substantially increased ERK2 activity. Both C7-caMEK1 and MDCK-C7F cells but not wild-type or mock-transfected MDCK-C7 cells express activated Mr 72,000 gelatinase A [matrix metalloproteinase (MMP)-2] as well as elevated levels of membrane type-1 MMP. Synthetic MMP inhibitors as well as recombinant tissue inhibitor of metalloproteinases 2 and 3 suppress the invasion of collagen gels and restore the capacity of C7-caMEK1 cells to form cysts, thereby implicating the membrane type-1 MMP/MMP-2 proteolytic system in epithelial cell invasiveness and loss of multicellular organization. Taken together, our data demonstrate that increased activity of the MEK1-ERK2 signaling module in MDCK-C7 cells is associated with failure of morphogenesis and expression of a highly invasive phenotype. Sustained activation of the MAPK cascade therefore results in the destabilization of the three-dimensional architecture and the conversion of polarized epithelial cells into migrating mesenchymal-like cells.




This article has been cited by other articles:


Home page
Cancer Res.Home page
N. Hijiya, Y. Tsukamoto, C. Nakada, L. Tung Nguyen, T. Kai, K. Matsuura, K. Shibata, M. Inomata, T. Uchida, A. Tokunaga, et al.
Genomic Loss of DUSP4 Contributes to the Progression of Intraepithelial Neoplasm of Pancreas to Invasive Carcinoma
Cancer Res., May 1, 2016; 76(9): 2612 - 2625.
[Abstract] [Full Text] [PDF]


Home page
J. Cell Sci.Home page
S. P. Barwe, A. Skay, R. McSpadden, T. P. Huynh, S. A. Langhans, L. J. Inge, and A. K. Rajasekaran
Na,K-ATPase {beta}-subunit cis homo-oligomerization is necessary for epithelial lumen formation in mammalian cells
J. Cell Sci., December 1, 2012; 125(23): 5711 - 5720.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Renal Physiol.Home page
V. Pollack, R. Sarkozi, Z. Banki, E. Feifel, S. Wehn, G. Gstraunthaler, H. Stoiber, G. Mayer, R. Montesano, F. Strutz, et al.
Oncostatin M-induced effects on EMT in human proximal tubular cells: differential role of ERK signaling
Am J Physiol Renal Physiol, November 1, 2007; 293(5): F1714 - F1726.
[Abstract] [Full Text] [PDF]


Home page
J. Cell Sci.Home page
M. Jorda, D. Olmeda, A. Vinyals, E. Valero, E. Cubillo, A. Llorens, A. Cano, and A. Fabra
Upregulation of MMP-9 in MDCK epithelial cell line in response to expression of the Snail transcription factor
J. Cell Sci., August 1, 2005; 118(15): 3371 - 3385.
[Abstract] [Full Text] [PDF]


Home page
J. Pharmacol. Exp. Ther.Home page
C. Sauvant, H. Holzinger, and M. Gekle
Proximal Tubular Toxicity of Ochratoxin A Is Amplified by Simultaneous Inhibition of the Extracellular Signal-Regulated Kinases 1/2
J. Pharmacol. Exp. Ther., April 1, 2005; 313(1): 234 - 241.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Cell Physiol.Home page
P. J. Boyd, J. Doyle, E. Gee, S. Pallan, and T. L. Haas
MAPK signaling regulates endothelial cell assembly into networks and expression of MT1-MMP and MMP-2
Am J Physiol Cell Physiol, February 3, 2005; 288(3): C659 - C668.
[Abstract] [Full Text] [PDF]


Home page
Mol. Cell. Biol.Home page
A. Karihaloo, S. Kale, N. D. Rosenblum, and L. G. Cantley
Hepatocyte Growth Factor-Mediated Renal Epithelial Branching Morphogenesis Is Regulated by Glypican-4 Expression
Mol. Cell. Biol., October 1, 2004; 24(19): 8745 - 8752.
[Abstract] [Full Text] [PDF]


Home page
Mol Cancer ResHome page
J. Pinkas, S. S. Martin, and P. Leder
Bcl-2-Mediated Cell Survival Promotes Metastasis of EpH4 {beta}MEKDD Mammary Epithelial Cells
Mol. Cancer Res., October 1, 2004; 2(10): 551 - 556.
[Abstract] [Full Text] [PDF]


Home page
J Biol ChemHome page
H. G. Munshi, Y. I. Wu, S. Mukhopadhyay, A. J. Ottaviano, A. Sassano, J. E. Koblinski, L. C. Platanias, and M. S. Stack
Differential Regulation of Membrane Type 1-Matrix Metalloproteinase Activity by ERK 1/2- and p38 MAPK-modulated Tissue Inhibitor of Metalloproteinases 2 Expression Controls Transforming Growth Factor-{beta}1-induced Pericellular Collagenolysis
J. Biol. Chem., September 10, 2004; 279(37): 39042 - 39050.
[Abstract] [Full Text] [PDF]


Home page
J. Am. Soc. Nephrol.Home page
G. Zhang, X. Cai, J. M. Lopez-Guisa, S. J. Collins, and A. A. Eddy
Mitogenic Signaling of Urokinase Receptor-Deficient Kidney Fibroblasts: Actions of an Alternative Urokinase Receptor and LDL Receptor-Related Protein
J. Am. Soc. Nephrol., August 1, 2004; 15(8): 2090 - 2102.
[Abstract] [Full Text] [PDF]


Home page
Cancer Res.Home page
T. Takino, H. Miyamori, Y. Watanabe, K. Yoshioka, M. Seiki, and H. Sato
Membrane Type 1 Matrix Metalloproteinase Regulates Collagen-Dependent Mitogen-Activated Protein/Extracellular Signal-Related Kinase Activation and Cell Migration
Cancer Res., February 1, 2004; 64(3): 1044 - 1049.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Cell Physiol.Home page
H. Schramek, E. Feifel, I. Marschitz, N. Golochtchapova, G. Gstraunthaler, and R. Montesano
Loss of active MEK1-ERK1/2 restores epithelial phenotype and morphogenesis in transdifferentiated MDCK cells
Am J Physiol Cell Physiol, August 4, 2003; 285(3): C652 - C661.
[Abstract] [Full Text] [PDF]


Home page
J Biol ChemHome page
H. Peinado, M. Quintanilla, and A. Cano
Transforming Growth Factor {beta}-1 Induces Snail Transcription Factor in Epithelial Cell Lines: MECHANISMS FOR EPITHELIAL MESENCHYMAL TRANSITIONS
J. Biol. Chem., May 30, 2003; 278(23): 21113 - 21123.
[Abstract] [Full Text] [PDF]


Home page
Mol. Biol. CellHome page
R. C. Bates and A. M. Mercurio
Tumor Necrosis Factor-{alpha} Stimulates the Epithelial-to-Mesenchymal Transition of Human Colonic Organoids
Mol. Biol. Cell, May 1, 2003; 14(5): 1790 - 1800.
[Abstract] [Full Text] [PDF]


Home page
J Biol ChemHome page
M.-R. Pan and W.-C. Hung
Nonsteroidal Anti-inflammatory Drugs Inhibit Matrix Metalloproteinase-2 via Suppression of the ERK/Sp1-mediated Transcription
J. Biol. Chem., September 6, 2002; 277(36): 32775 - 32780.
[Abstract] [Full Text] [PDF]


Home page
Cancer Res.Home page
J. Pinkas and P. Leder
MEK1 Signaling Mediates Transformation and Metastasis of EpH4 Mammary Epithelial Cells Independent of an Epithelial to Mesenchymal Transition
Cancer Res., August 15, 2002; 62(16): 4781 - 4790.
[Abstract] [Full Text] [PDF]


Home page
PhysiologyHome page
H. Schramek
MAP Kinases: From Intracellular Signals to Physiology and Disease
Physiology, April 1, 2002; 17(2): 62 - 67.
[Abstract] [Full Text] [PDF]


Home page
Genes Dev.Home page
A. Schulze, K. Lehmann, H. B.J. Jefferies, M. McMahon, and J. Downward
Analysis of the transcriptional program induced by Raf in epithelial cells
Genes & Dev., April 15, 2001; 15(8): 981 - 994.
[Abstract] [Full Text]


Home page
IOVSHome page
A. Zubilewicz, C. Hecquet, J.-C. Jeanny, G. Soubrane, Y. Courtois, and F. Mascarelli
Proliferation of CECs Requires Dual Signaling through Both MAPK/ERK and PI 3-K/Akt Pathways
, February 1, 2001; 42(2): 488 - 496.
[Abstract] [Full Text]


Home page
JCBHome page
H. Reuveni, T. Geiger, B. Geiger, and A. Levitzki
Reversal of the Ras-Induced Transformed Phenotype by Hr12, a Novel Ras Farnesylation Inhibitor, Is Mediated by the Mek/ERK Pathway
J. Cell Biol., December 11, 2000; 151(6): 1179 - 1192.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Cell Physiol.Home page
I. Marschitz, J. Lechner, I. Mosser, M. Dander, R. Montesano, and H. Schramek
Differential expression of cell-cell adhesion proteins and cyclin D in MEK1-transdifferentiated MDCK cells
Am J Physiol Cell Physiol, November 1, 2000; 279(5): C1472 - C1482.
[Abstract] [Full Text] [PDF]


Home page
JCBHome page
K. Hotary, E. Allen, A. Punturieri, I. Yana, and S. J. Weiss
Regulation of Cell Invasion and Morphogenesis in a Three-Dimensional Type I Collagen Matrix by Membrane-Type Matrix Metalloproteinases 1, 2, and 3
J. Cell Biol., June 12, 2000; 149(6): 1309 - 1323.
[Abstract] [Full Text] [PDF]


Home page
J. Pharmacol. Exp. Ther.Home page
M. Gekle, G. Schwerdt, R. Freudinger, S. Mildenberger, D. Wilflingseder, V. Pollack, M. Dander, and H. Schramek
Ochratoxin A Induces JNK Activation and Apoptosis in MDCK-C7 Cells at Nanomolar Concentrations
J. Pharmacol. Exp. Ther., June 1, 2000; 293(3): 837 - 844.
[Abstract] [Full Text]




HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cell Growth & Differentiation
Copyright © 1999 by the American Association of Cancer Research.