c-Jun NH2-terminal kinase 2 is required for Ras transformation independently of activator protein 1.
Active Ras oncogene is expressed in approximately 30% of human cancers. Yet, very little is known about the molecular mechanisms responsible for its transforming potential. Here, we show that H-Ras-mediated transformation requires isoform 2 of the c-Jun-NH(2)-terminal kinase (JNK). H-Ras-transduced JNK2-deficient (Jnk2-/-) murine embryonic fibroblasts (MEFs) were severely inhibited in colony formation and growth in soft agar in vitro as well as in tumor formation in immunodeficient mice as compared with corresponding Jnk1-/- and wild-type MEFs. Accordingly, the RNA interference-based depletion of JNK2 form wild-type MEFs also resulted in defective Ras transformation. The extra barrier against H-Ras transformation in Jnk2-/- MEFs was not due to their inability to inactivate p53 signaling because all JNK2-deficient MEF lines had lost p19(Arf). Furthermore, expression of the E6 protein of the human papilloma virus failed to overcome the transformation defect. It could, however, be overcome by coexpression of H-Ras with the SV40 large T antigen or c-Myc. Surprisingly, the H-Ras-transduced JNK2-deficient MEFs exhibited higher activity of activator protein-1 and higher levels of c-Jun expression compared with H-Ras-transduced JNK1-deficient or wild-type cells, indicating that the key target of JNK2 during Ras transformation was divergent from activator protein-1. These results clearly show that a single kinase, JNK2, could control Ras transformation and thus point out a vulnerable control point that may prove important for the tumor development in general.
Nielsen
Christina
C
Apoptosis Department and Centre for Genotoxic Stress, Institute of Cancer Biology, Danish Cancer Society, Strandboulevarden 49, DK-2100 Copenhagen, Denmark.
Thastrup
Jacob
J
Bøttzauw
Trine
T
Jäättelä
Marja
M
Kallunki
Tuula
T
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D011905:Genes, ras; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D048056:Mitogen-Activated Protein Kinase 9 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D034622:RNA Interference; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014161:Transduction, Genetic; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
D018808:Transcription Factor AP-1; D048056:Mitogen-Activated Protein Kinase 9; D018631:ras Proteins