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The tumor suppressor p16INK4a prevents cell transformation through inhibition of c-Jun phosphorylation and AP-1 activity

Nature Structural & Molecular Biology volume 12, pages 699–707 (2005)Cite this article

Abstract

Inactivation of the p16INK4a 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 p16INK4a inhibition of neoplastic transformation and UV-induced skin cancer. We show that p16INK4a 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 p16INK4a 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.

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Figure 1: In vitro and in vivo interaction of p16INK4a with JNK proteins.
Figure 2: Binding of p16INK4a and JNK1 or JNK3.
Figure 3: Predicted model of the p16INK4a–JNK3 complex.
Figure 4: Regulation of JNK activity by p16INK4a.
Figure 5: Suppression of AP-1 activity through the p16INK4a inhibition of UV-induced JNK activity.
Figure 6: Interference of p16INK4a with JNK1 and c-Jun binding and nuclear translocation of phosphorylated JNK.
Figure 7: p16INK4a inhibition of focus formation mediated by H-Ras–JNK.

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Acknowledgements

This work was supported in part by the Hormel Foundation and grants from the US National Institutes of Health. We thank R. Davis for JNKs plasmids, C. Chen and Z. Kiss for Rb−/− and CHO-K1 cell lines and A. Hansen for secretarial assistance.

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Authors and Affiliations

  1. Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, 55912, Minnesota, USA

    Bu Young Choi, Hong Seok Choi, Yong-Yeon Cho, Feng Zhu, Bong Seok Kang, Svetlana P Ermakova, Wei-Ya Ma, Ann M Bode & Zigang Dong

  2. Laboratory of Molecular Biology, C&C Research Labs, Hwasung-City, 445-970, Republic of Korea

    Bu Young Choi & Kwangseok Ko

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Supplementary information

Supplementary Fig. 1

Specific binding assay of JNK1 or JNK3 and p16INK4a. (PDF 88 kb)

Supplementary Fig. 2

Sequence similarity of JNKs and interaction with p16INK4a. (PDF 1694 kb)

Supplementary Methods (PDF 131 kb)

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Choi, B., Choi, H., Ko, K. et al. The tumor suppressor p16INK4a prevents cell transformation through inhibition of c-Jun phosphorylation and AP-1 activity. Nat Struct Mol Biol 12, 699–707 (2005). https://doi.org/10.1038/nsmb960

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