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Nucleolin inhibits Hdm2 by multiple pathways leading to p53 stabilization

Oncogene volume 25, pages 7274–7288 (2006)Cite this article

Abstract

Nucleolin is a c-Myc-induced gene product with defined roles in ribosomal RNA processing and the inhibition of chromosomal DNA replication following stress. Here we find that changes in nucleolin protein levels in unstressed cells cause parallel changes in the amount of p53 protein. Alterations in p53 levels arise from nucleolin binding to the p53 antagonist Hdm2, resulting in the inhibition of both p53 ubiquitination and Hdm2 auto-ubiquitination. Nucleolin does not alter p53 ubiquitination by human papillomavirus E6, indicating that the effect is specific for Hdm2. Although the inhibition of ligase activity would be expected to stabilize Hdm2, we instead find that nucleolin also reduces Hdm2 protein levels, demonstrating that nucleolin inhibits Hdm2 using multiple mechanisms. Increases in nucleolin levels in unstressed cells led to higher expression of p21cip1/waf1, a reduced rate of cellular proliferation, and an increase in apoptosis. Thus, nucleolin has a number of properties in common with the tumor suppressor ARF (alternate reading frame). We propose that nucleolin, like ARF, responds to hyperproliferative signals by upregulation of p53 through Hdm2 inhibition.

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Acknowledgements

We thank Moshe Oren for various constructs and reagents for the cell-free ubiquitination assay, Michele Pagano for the His-Ub vector, Bert Vogelstein for the Hdm2-wt expression plasmid and the HCT116-wt and HCT116-ko cell lines. We also thank A Wilson, P Bhatt and V Vassin for critical comments on the manuscript, and Elena Sokolova for technical assistance. JAB was supported by Philip Morris USA Inc. (15-B0001-42171), the DOD Breast Cancer Research Program (DAMD17-03-1-0299), NIH grant AI29963, and the NYU Cancer Institute and the Rita J and Stanley Kaplan Comprehensive Cancer Center (NCI P30CA16087).

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  1. Y Daniely

    Present address: Gamida-Cell, Ltd, 5 Nahum Hafzadi Street, Jerusalem, 95484, Israel

Authors and Affiliations

  1. Department of Biochemistry and New York University Cancer Institute, New York University School of Medicine, New York, NY, USA

    A Saxena, C J Rorie, D Dimitrova, Y Daniely & J A Borowiec

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  1. A Saxena
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Correspondence to J A Borowiec.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Saxena, A., Rorie, C., Dimitrova, D. et al. Nucleolin inhibits Hdm2 by multiple pathways leading to p53 stabilization. Oncogene 25, 7274–7288 (2006). https://doi.org/10.1038/sj.onc.1209714

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