The tumor suppressor p16(INK4a) prevents cell transformation through inhibition of c-Jun phosphorylation and AP-1 activity.

Abstract

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.

• Authors: Bu Young Choi, Hong Seok Choi, Kwangseok Ko, Yong-Yeon Cho, Feng Zhu, Bong Seok Kang, Svetlana P Ermakova, Wei-Ya Ma, Ann M Bode, Zigang Dong
• Journal: Nature structural & molecular biology (Nat Struct Mol Biol) Vol. 12 Issue 8 Pg. 699-707 (Aug 2005) ISSN: 1545-9993 [Print] United States
• PMID: 16007099 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Cyclin-Dependent Kinase Inhibitor p16
• Transcription Factor AP-1
• Glutathione Transferase
• Mitogen-Activated Protein Kinase 10

Topics

• Animals
• Cell Line, Tumor
• Cell Transformation, Neoplastic (metabolism)
• Cyclin-Dependent Kinase Inhibitor p16 (metabolism)
• Fluorescent Antibody Technique
• Genetic Vectors
• Glutathione Transferase
• Humans
• Immunoblotting
• Melanoma (metabolism)
• Mice
• Mitogen-Activated Protein Kinase 10 (metabolism)
• Models, Molecular
• Phosphorylation
• Protein Binding
• Signal Transduction (physiology)
• Skin Neoplasms (metabolism)
• Transcription Factor AP-1 (metabolism)
• Two-Hybrid System Techniques