1. ¹Laboratory of Cell Regulation and Carcinogenesis, NCI, NIH, Bethesda, MD, USA
2. ²Diabetes Branch, NIDDK, NIH, Bethesda, MD, USA

Correspondence: Dr PR Arany, Harvard School of Dental Medicine, Harvard University, 188 Longwood Avenue, REB 203, Boston, MA 2115, USA. E-mail: arany@fas.harvard.edu; Dr SG Rane, Email: ranes@mail.nih.gov

³Current address: Programs in Biological Sciences in Dental Medicine—Leder Medical Sciences and Oral and Maxillofacial Pathology, Harvard School of Dental Medicine, Boston, MA, USA

Received 27 July 2007; Revised 14 September 2007; Accepted 1 October 2007; Published online 22 October 2007.

Abstract

The ability of transforming growth factor- (TGF-) to modulate various effects on distinct cell lineages has been a central feature of its multi-faceted nature. The purpose of this study was to access the effects of deletion of a key TGF- signal transducer, Smad3, on MAPK activation and v-Ras^Ha-transformation of primary mouse embryonic fibroblasts (MEFs). We observe reduced TGF-1 and v-ras^Ha mediated activation of the JNK and ERK MAPK pathway upon ablation of Smad3. Further, Smad3-deficient MEFs demonstrate resistance to v-ras^Ha-induced transformation while the absence of Smad3 results in increased inhibition of farnesyl transferase activity. Taken together, these observations demonstrate that the absence of Smad3 protects fibroblasts from oncogenic transformation by (i) augmenting farnesyl transferase inhibition and (ii) suppressing the Ras—JNK MAPK pathway. These results provide new insights into the molecular mechanisms involved in v-Ras^Ha oncogene-induced mesenchymal phenotypic transformation.