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Signaling and Regulation

Essential Role of Raf in Ras Transformation and Deregulation of Matrix Metalloproteinase Expression in Ovarian Epithelial Cells¹

¹ Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC and ² Institute of Pathology, Charité Humboldt University, Berlin, Germany

Requests for reprints: Channing J. Der, Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, CB 7295, Chapel Hill, NC 27599-7295. Phone: (919) 966-5634; Fax: (919) 966-0162. E-mail: cjder{at}med.unc.edu

Oncogenic Ras mediates its actions through activation of multiple downstream effector signaling cascades, which in turn regulate transcription factor activation and cause changes in gene expression. However, there exist striking cell type differences in effector pathways that are activated by Ras, in which effectors are sufficient or necessary to promote Ras oncogenesis, and in the gene targets of Ras transformation. Therefore, we evaluated the contribution of specific effectors in mediating H-Ras(12V) transformation of rat ovarian surface epithelial (ROSE) cells and up-regulation of matrix metalloproteinase (MMP) gene expression. First, we found that Raf activation alone was sufficient to partially reconstitute H-Ras(12V)-mediated morphological and growth transformation. However, Raf-independent signaling pathways are required for full Ras transformation of ROSE cells. Ras transformation did not cause activation of the phosphatidylinositol 3-kinase (PI3K) target, Akt, and PI3K inhibition did not reverse morphological transformation but did inhibit growth in soft agar, indicating a role for basal PI3K activity in anchorage-independent growth. Second, we determined that MMP-3 and MMP-10, but surprisingly not MMP-9, gene expression was up-regulated in Ras-transformed ROSE cells. Raf activation alone was fully sufficient and necessary for MMP transcriptional up-regulation. However, up-regulation of MMP-3 or MMP-10 gene expression alone is not critical for Ras-mediated transformation. In summary, in contrast to other epithelial cell types, Raf is a major effector for Ras transformation of ovarian epithelial cells.

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