Signaling pathways in Ras-mediated tumorigenicity and metastasis

Webb, C. P., Van Aelst, L., Wigler, M. H., Woude, G. F. (July 1998) Signaling pathways in Ras-mediated tumorigenicity and metastasis. Proc Natl Acad Sci U S A, 95 (15). pp. 8773-8. ISSN 0027-8424 (Print)

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Abstract

The effector domain mutants of oncogenic Ras, V12S35 Ras, V12G37 Ras, and V12C40 Ras were tested for their abilities to mediate tumorigenic and metastatic phenotypes in athymic nude mice when expressed in NIH 3T3 fibroblasts. All mutants displayed comparable tumorigenic properties, but only the mutant that activates the Raf-mitogen-activated protein kinase kinase (MEK)-extracellular regulated kinase (ERK) 1/2 pathway, V12S35 Ras, induced tumors in the experimental metastasis assay. Furthermore, direct activation of the MEK-ERK1/2 pathway in NIH 3T3 cells by mos or a constitutively active form of MEK was sufficient to induce metastasis whereas R-Ras, which fails to activate the ERK1/2 pathway, is tumorigenic but nonmetastatic. The subcutaneous tumors and lung metastases derived from V12S35 Ras-transformed NIH 3T3 cells expressed higher levels of activated ERK1/2 in culture when compared with the parental cellular pool before injection, indicating that selection for cells with higher levels of activated ERK1/2 occurred during tumor growth and metastasis. By contrast, cells explanted from V12G37-Ras or V12C40-Ras-induced tumors did not show changes in the level of ERK1/2 activation when compared with the parental cells. When tumor-explanted cell lines derived from each of the effector domain mutants were passaged one additional time in vivo, all mediated rapid tumor growth, but, again, only cells derived from V12S35 Ras-tumors formed numerous metastatic lesions within the lung. These results show that the metastatic properties of the Ras effector domain mutants segregate, and that, whereas Ras-mediated tumorigenicity can arise independently of ERK1/2 activation, experimental metastasis appears to require constitutive activation of the ERK1/2 pathway.

Item Type:	Paper
Uncontrolled Keywords:	3T3 Cells Animals Ca(2+)-Calmodulin Dependent Protein Kinase metabolism Cell Transformation, Neoplastic Enzyme Activation Humans Mice Mice Nude Mutation Neoplasm Metastasis Oncogene Protein p21(ras) genetics physiology Phosphorylation Signal Transduction
Subjects:	bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > RAS bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene expression bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene regulation bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene regulation bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > oncogene
CSHL Authors:	Van Aelst, Linda Wigler, Michael H.
Communities:	CSHL labs > Van Aelst lab CSHL labs > Wigler lab
Depositing User:	CSHL Librarian
Date:	21 July 1998
Date Deposited:	06 Apr 2012 15:09
Last Modified:	09 Nov 2017 17:20
PMCID:	PMC21152
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/25984

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