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Modulation of p53 and MDM2 activity by novel interaction with Ras-GAP binding proteins (G3BP)

Oncogene volume 26, pages 4209–4215 (2007)Cite this article

Abstract

Inactivation of the p53 tumor suppressor pathway is a critical step in human tumorigenesis. In addition to mutations, p53 can be functionally silenced through its increased degradation, inhibition of its transcriptional activity and/or its inappropriate subcellular localization. Using a proteomic approach, we have found that members of the Ras network of proteins, Ras-GTPase activating protein-SH3-domain-binding proteins 1 and 2 (G3BP1 and 2), bind to p53 in vitro and in vivo. Our data show that expression of G3BPs leads to the redistribution of p53 from the nucleus to the cytoplasm. The G3BP2 isoform additionally associated with murine double minute 2 (MDM2), a negative regulator of p53. G3BP2 expression resulted in significant reduction in MDM2-mediated p53 ubiquitylation and degradation. Interestingly, MDM2 was also stabilized in G3BP2-expressing cells and its ability to ubiquitylate itself was compromised. Accordingly, short hairpin RNA (shRNA)-mediated knockdown of G3BP2 caused a reduction in MDM2 protein levels. Furthermore, expression of shRNA targeting either G3BP1 or G3BP2 in human cancer cell lines resulted in marked upregulation of p53 levels and activity. Our results suggest that both G3BP isoforms may act as negative regulators of p53.

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Acknowledgements

We thank Dr Bert Vogelstein for his generous gift of cells used in this study, and Dr Yang Shi for the pBS/U6 plasmid. We also thank the Biological Analysis Facility Care (NIEHS 5P30ES00002) for their expertise. This work was funded by the National Institutes of Health RO1CA85679-02 to ZMY. DW is supported by the Ruth L Kirschstein National Research Service Award (CA009078). MMK is supported by National Institutes of Health T32ES007155.

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Author notes

  1. D Wiederschain

    Present address: 4Current address: Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.,

  2. M M Kim and D Wiederschain: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA, USA

    M M Kim, D Wiederschain, E Hansen & Z-M Yuan

  2. School of Biomolecular and Biomedical Sciences, Griffith University, Nathan, Queensland, Australia

    D Kennedy

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  1. M M Kim
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  2. D Wiederschain
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Correspondence to Z-M Yuan.

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Kim, M., Wiederschain, D., Kennedy, D. et al. Modulation of p53 and MDM2 activity by novel interaction with Ras-GAP binding proteins (G3BP). Oncogene 26, 4209–4215 (2007). https://doi.org/10.1038/sj.onc.1210212

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