Deficiency of c-Jun-NH(2)-terminal kinase-1 in mice enhances skin tumor development by 12-O-tetradecanoylphorbol-13-acetate.
The c-Jun NH(2)-terminal kinase (JNK) has been implicated in regulating cell survival, apoptosis, and transformation. However, the distinct role of JNK isoforms in regulating tumor development is not yet clear. We have found previously that skin tumor formation induced by the tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA), is suppressed in JNK2-deficient (Jnk2(-/-)) mice. Here, we show that JNK1-deficient (Jnk1(-/-)) mice are more susceptible to TPA-induced skin tumor development than wild-type mice. The rate of tumor development in Jnk1(-/-) mice was significantly more rapid than that observed in wild-type mice (P < 0.0001). At the end of 33 weeks of TPA promotion, the number of skin tumors and tumors >1.5 mm in diameter per mouse in Jnk1(-/-) mice was significantly increased by 71% (P < 0.03) and 82% (P < 0.03), respectively, relative to the wild-type mice. Furthermore, the carcinoma incidence and the number of carcinomas per mouse were also higher in Jnk1(-/-) mice. Strikingly, Jnk1(-/-) mouse skin was more sensitive to TPA-induced AP-1 DNA binding activity and phosphorylation of extracellular signal-regulated kinases and Akt, which are two important survival signaling components. These results suggest that JNK1 is a crucial suppressor of skin tumor development.
She
Qing-Bai
QB
The Hormel Institute, University of Minnesota, Austin, Minnesota 55912, USA.
Chen
Nanyue
N
Bode
Ann M
AM
Flavell
Richard A
RA
Dong
Zigang
Z
D000818:Animals; D004247:DNA / Q000378:metabolism; D051379:Mice; D048055:Mitogen-Activated Protein Kinase 8; D048056:Mitogen-Activated Protein Kinase 9; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*; D010212:Papilloma / Q000139:chemically induced; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000139:chemically induced*; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity*; D018808:Transcription Factor AP-1 / Q000378:metabolism
D011518:Proto-Oncogene Proteins; D018808:Transcription Factor AP-1; D004247:DNA; D048056:Mitogen-Activated Protein Kinase 9; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate