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 kinase (PSK) c-jun expression is constitutive while c-fos expression is attenuated. This alteration prompted us to determine whether oncogene transformation would render cells differentially sensitive to growth inhibition by a dominant negative mutant of c-jun, TAM 67. Growth inhibition was observed in three types of assays: (1) transfection of TAM 67 into cells stably transformed by a variety of oncogenes, (2) cotransfection of TAM 67 with oncogene expression plasmids into NIH3T3 cells and (3) titration of oncogene-expressing retroviruses on cells stably expressing TAM 67. The results clearly demonstrate that Raf-1 dependent oncogenes, which include receptor protein tyrosine kinases (PTKs)-, intracellular PTKs- and Ras-derived genes share the Raf phenotype of constitutive c-jun expression, attenuated c-fos induction, and high sensitivity 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 pattern of altered growth regulation in oncogene transformed fibroblast cell lines highlights the potential usefulness of c-jun based inhibitors for control of tumor cell growth.
Laboratory of Viral Carcinogenesis, National Cancer Institute, Frederick Cancer Research and Development Center, Maryland 21702-1201.
U R
UR
Rapp
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J
Troppmair
T
T
Beck
M J
MJ
Birrer
D016475:3T3 Cells; D000818:Animals; D002455:Cell Division / Q000235:genetics*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D005799:Genes, Dominant; D016758:Genes, jun; D051379:Mice; D009154:Mutation; D027384:Oncogene Proteins v-raf; D009857:Oncogenes; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D051381:Rats; D015682:Retroviridae Proteins, Oncogenic / Q000502:physiology*
D015682:Retroviridae Proteins, Oncogenic; D011505:Protein-Tyrosine Kinases; D027384:Oncogene Proteins v-raf