title: Smad3 deficiency inhibits v-ras-induced transformation by suppression of JNK MAPK signaling and increased farnesyl transferase inhibition.
abstract: The ability of transforming growth factor-beta (TGF-beta) 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-beta signal transducer, Smad3, on MAPK activation and v-Ras(Ha)-transformation of primary mouse embryonic fibroblasts (MEFs). We observe reduced TGF-beta1 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.
authors.affiliation: Laboratory of Cell Regulation and Carcinogenesis, NCI, NIH, Bethesda, MD, USA. arany@fas.harvard.edu
authors.forename: P R
authors.initials: PR
authors.lastname: Arany
authors.forename: S G
authors.initials: SG
authors.lastname: Rane
authors.forename: A B
authors.initials: AB
authors.lastname: Roberts
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000378:metabolism*; D000818:Animals; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D051900:Smad3 Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D019076:Transgenes / Q000235:genetics*
chemical_list: D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D015689:Oncogene Protein p21(ras)