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

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

doi:10.1038/nsmb960

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

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

The Hormel Institute

Research output: Contribution to journal › Article › peer-review

61 Scopus citations

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.

Original language	English (US)
Pages (from-to)	699-707
Number of pages	9
Journal	Nature Structural and Molecular Biology
Volume	12
Issue number	8
DOIs	https://doi.org/10.1038/nsmb960
State	Published - Aug 2005

Bibliographical note

Funding Information:
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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title = "The tumor suppressor p16INK4a prevents cell transformation through inhibition of c-Jun phosphorylation and AP-1 activity",

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 p16 INK4a 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.",

author = "Bu, {Young Choi} and Hong, {Seok Choi} and Kwangseok Ko and Cho, {Yong Yeon} and Feng Zhu and Bong, {Seok Kang} and Ermakova, {Svetlana P.} and Wei-Ya Ma and Bode, {Ann M.} and Zigang Dong",

note = "Funding Information: 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.",

year = "2005",

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T1 - The tumor suppressor p16INK4a prevents cell transformation through inhibition of c-Jun phosphorylation and AP-1 activity

AU - Bu, Young Choi

AU - Hong, Seok Choi

AU - Ko, Kwangseok

AU - Cho, Yong Yeon

AU - Zhu, Feng

AU - Bong, Seok Kang

AU - Ermakova, Svetlana P.

AU - Ma, Wei-Ya

AU - Bode, Ann M.

AU - Dong, Zigang

N1 - Funding Information: 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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N2 - 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 p16 INK4a 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.

AB - 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 p16 INK4a 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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