The tumor suppressor p16(INK4a) prevents cell transformation through inhibition of c-Jun phosphorylation and AP-1 activity.
Inactivation of the p16(INK4a) tumor suppressor protein is critical for the development of human cancers, including human melanoma. However, the molecular basis of the protein's inhibitory effect on cancer development is not clear. Here we investigated a possible mechanism for p16(INK4a) inhibition of neoplastic transformation and UV-induced skin cancer. We show that p16(INK4a) suppresses the activity of c-Jun N-terminal kinases (JNKs) and that it binds to the glycine-rich loop of the N-terminal domain of JNK3. Although p16(INK4a) does not affect the phosphorylation of JNKs, its interaction with JNK inhibits c-Jun phosphorylation induced by UV exposure. This, in turn, interferes with cell transformation promoted by the H-Ras-JNK-c-Jun-AP-1 signaling axis.
Choi
Bu Young
BY
Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, Minnesota 55912, USA.
Choi
Hong Seok
HS
Ko
Kwangseok
K
Cho
Yong-Yeon
YY
Zhu
Feng
F
Kang
Bong Seok
BS
Ermakova
Svetlana P
SP
Ma
Wei-Ya
WY
Bode
Ann M
AM
Dong
Zigang
Z
D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D005822:Genetic Vectors; D005982:Glutathione Transferase; D006801:Humans; D015151:Immunoblotting; D008545:Melanoma / Q000378:metabolism*; D051379:Mice; D048057:Mitogen-Activated Protein Kinase 10 / Q000378:metabolism*; D008958:Models, Molecular; D010766:Phosphorylation; D011485:Protein Binding; D015398:Signal Transduction / Q000502:physiology*; D012878:Skin Neoplasms / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
D019941:Cyclin-Dependent Kinase Inhibitor p16; D018808:Transcription Factor AP-1; D005982:Glutathione Transferase; D048057:Mitogen-Activated Protein Kinase 10