TRANSFORMATION BY RAF AND OTHER ONCOGENES RENDERS CELLS DIFFERENTIALLY SENSITIVE TO GROWTH-INHIBITION BY A DOMINANT-NEGATIVE C-JUN MUTANT

In NIH3T3 cells expressing active Raf-1 protein serine/threonine kinas e (PSK) c-jun expression is constitutive while c-fos expression is att enuated. This alteration prompted us to determine whether oncogene tra nsformation would render cells differentially sensitive to growth inhi bition by a dominant negative mutant of c-jun, TAM 67. Growth inhibiti on was observed in three types of assays: (1) transfection of TAM 67 i nto cells stably transformed by a variety of oncogenes, (2) cotransfec tion of TAM 67 with oncogene expression plasmids into NIH3T3 cells and (3) titration of oncogene-expressing retroviruses on cells stably exp ressing TAM 67. The results clearly demonstrate that Raf-1 dependent o ncogenes, which include receptor protein tyrosine kinases (PTKs)-, int racellular PTKs- and Ras-derived genes share the Raf phenotype of cons titutive c-jun expression, attenuated c-fos induction, and high sensit ivity to growth suppression by TAM 67. Additionally, the intracellular PSK oncogene, mos and the nuclear oncogenes c-myc, c-fos, and SV40 T antigen were TAM 67-sensitive for transformation This universal patter n of altered growth regulation in oncogene transformed fibroblast cell lines highlights the potential usefulness of c-jun based inhibitors f or control of tumor cell growth.