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Modification of p53 with O-linked N-acetylglucosamine regulates p53 activity and stability

Nature Cell Biology volume 8, pages 1074–1083 (2006)Cite this article

An Addendum to this article was published on 01 December 2007

An Erratum to this article was published on 01 April 2007

Abstract

Post-translational addition of O-linked N-acetylglucosamine (O-GlcNAc) to p53 is known to occur, but the site of O-GlcNAcylation and its effects on p53 are not understood. Here, we show that Ser 149 of p53 is O-GlcNAcylated and that this modification is associated with decreased phosphorylation of p53 at Thr 155, which is a site that is targeted by the COP9 signalosome, resulting in decreased p53 ubiquitination. Accordingly, O-GlcNAcylation at Ser 149 stabilizes p53 by blocking ubiquitin-dependent proteolysis. Our results indicate that the dynamic interplay between O-GlcNAc and O-phosphate modifications coordinately regulate p53 stability and activity.

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Figure 1: Streptozotocin, an O-GlcNAcase inhibitor, decreases cell viability and increases the accumulation and O-GlcNAcylation of p53 in MCF-7 cells.
Figure 2: O-GlcNAcylation of p53 by STZ treatment reduces p53 ubiquitination and p53–Mdm2 interactions in MCF-7 cells.
Figure 3: O-GlcNAcylation of p53 by STZ treatment inhibits phosphorylation of p53 at Thr 155 in MCF-7 cells.
Figure 4: Tumour suppressor p53 is modified by O-GlcNAc at Ser 149 in MCF-7 cells.
Figure 5: Mutation of the p53 O-GlcNAcylation site (Ser 149) abrogates STZ-induced p53 accumulation in MCF-7 cells.
Figure 6: Mutation of the p53 O-GlcNAcylation site (Ser 149) abrogates STZ-induced p53 accumulation in p53-knockout H1299 cells.

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Acknowledgements

This work was supported by grants from the Korea Science and Engineering Foundation through the center for Protein Network Research Center at Yonsei University (R112000078020010); the Glycomics Research Program of Ministry of Science and Technology (2004-02130 to J.W.C.); a Korea Research Foundation Grant (KRF-2004-005-C00112), through the Yonsei Biomedical Science and Technology Initiative Program; and, in part, by a grant from the Korea Health 21 R&D Project, via the Ministry of Health & Welfare, Republic of Korea (03-PJ10-PG6-GP01-0002). This work was also supported, in part, by Brain Korea 21 project. This work was made possible through the use of research facilities in the Yonsei Center for Biotechnology.

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  1. Department of Biology, Yonsei University, 134 Shinchon-dong, Seodaemun-gu, Seoul, 120-749, Korea

    Won Ho Yang, Ji Eun Kim, Jung Won Ju, Hoe Suk Kim & Jin Won Cho

  2. Protein Network Research Center, Yonsei University, 134 Shinchon-dong, Seodaemun-gu, Seoul, 120-749, Korea

    Won Ho Yang, Ji Eun Kim, Hyung Wook Nam, Jung Won Ju, Hoe Suk Kim, Yu Sam Kim & Jin Won Cho

  3. Department of Biochemistry, Yonsei University, 134 Shinchon-dong, Seodaemun-gu, Seoul, 120-749, Korea

    Hyung Wook Nam & Yu Sam Kim

  4. ProteomeTech, Yonsei Dairy Building, Seodaemun-gu, Seoul, 120-749, Korea

    Yu Sam Kim & Jin Won Cho

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Experiments were designed and data were analysed by W.H.Y. Mass spectrometry was performed by J.E.K., H.W.N. and Y.S.K. Data were analysed and interpreted by J.W.J., H.S.K. and J.W.C. The paper was written by J.W.C.

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Correspondence to Jin Won Cho.

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Yang, W., Kim, J., Nam, H. et al. Modification of p53 with O-linked N-acetylglucosamine regulates p53 activity and stability. Nat Cell Biol 8, 1074–1083 (2006). https://doi.org/10.1038/ncb1470

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