Induction of the nuclear proto-oncogene c-fos by the phorbol ester TPA and v-H-Ras.
TPA is known to cooperate with an activated Ras oncogene in the transformation of rodent fibroblasts, but the biochemical mechanisms responsible for this effect have not been established. In the present study we used c-fos promoter-luciferase constructs as reporters, in transient transfection assays, in NIH3T3 cells to assess the mechanism of this cooperation. We found a marked synergistic interaction between TPA and a transfected v-Ha-ras oncogene in the activation of c-fos promoter and SRE. SRE has binding sites for TCF and SRF. A dominant-negative Ras (ras-N17) inhibited the TPA-Ras synergy by blocking the PKC-MAPK-TCF pathway. Dominant-negative RhoA and Rac1 (but not Cdc42Hs) inhibited the TPA-Ras synergy by blocking the Ras-Rho-SRF signaling pathway. Constitutively active PKCalpha and PKCepsilon showed synergy with v-Ras. These results suggest that the activation of two distinct pathways such as Ras-Raf-ERK-TCF pathway and Rho-SRF pathway are responsible for the induction of c-fos by TPA and Ras in mitogenic signaling pathways.
Kazi
Julhash U
JU
Biomedical Research Center for Signal Transduction Networks, Department of Chemistry, Inha University, Incheon 402-751, Korea.
Soh
Jae-Won
JW
D000818:Animals; D019556:COS Cells; D002467:Cell Nucleus / Q000187:drug effects / Q000235:genetics*; D002522:Chlorocebus aethiops; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D011905:Genes, ras; D051379:Mice; D041681:NIH 3T3 Cells; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics* / Q000378:metabolism*; D027602:Serum Response Element; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D016760:Proto-Oncogene Proteins c-fos; D011493:Protein Kinase C; D015689:Oncogene Protein p21(ras); D020741:rho GTP-Binding Proteins; D013755:Tetradecanoylphorbol Acetate