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Suppression of Skin Tumorigenesis in c-Jun NH₂-Terminal Kinase-2-Deficient Mice¹

The Hormel Institute, University of Minnesota, Austin, Minnesota 55912 [N. C., M. N., Q-B. S., W-Y. M., A. M. B., Z. D.]; Department of Pathology, Hilton 11, Mayo Clinic, Rochester, Minnesota 55905 [L. W.]; and Department and Section of Immunology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06520 [R. A. F.]

Previous studies have shown that c-Jun NH₂-terminal kinase (JNK) belongs to the mitogen-activated protein kinase (MAPK) family of signal transduction components that are rapidly initiated and activated by many extracellular stimuli. However, the potential role of JNK in mediating tumor promotion and carcinogenesis is unclear. We show here that in JNK2-deficient (Jnk2^-/-) mice, the multiplicity of papillomas induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) was lower than that in wild-type mice. Papillomas on wild-type mice grew rapidly and were well vascularized compared with Jnk2^-/- mice. After the 12th week of TPA treatment, the mean number of tumors per mouse was 4.13–4.86 in wild-type mice but only 1.13–2.5 in Jnk2^-/- mice. TPA induced phosphorylation of extracellular signal-regulated kinases and activator protein-1 DNA binding activity in wild-type mice, but the phosphorylation of extracellular signal-regulated kinases and activator protein-1 DNA binding were inhibited in Jnk2^-/- mice. These data suggest that JNK2 is critical in the tumor promotion process.

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