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Ubiquitous Induction of p53 in Tumor Cells by Antisense Inhibition of MDM2 Expression

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Abstract

Background

The MDM2 oncogene functions as a negative feedback regulator of the p53 tumor suppressor. Abnormal expression of MDM2 in tumors may attenuate the p53-mediated growth arrest and apoptosis response, resulting in increased cell proliferation and resistance to chemotherapy.

Materials and Methods

We have developed phosphorothioate antisense oligodeoxynucleotides optimized for inhibition of MDM2 expression and investigated the role of MDM2 in a large panel of tumor cell lines.

Results

Inhibition of MDM2 expression in 15 tumor types containing wild-type p53 results in a significant induction of nuclear p53 accumulation. The increase in p53 level is due to prolonged half-life and is associated with an increase in p53 transcriptional activity, growth inhibition, or apoptosis. Inhibition of MDM2 expression is also sufficient to induce nuclear p53 accumulation in several cell lines with cytoplasmic p53.

Conclusions

The MDM2 negative feedback loop is important for maintenance of p53 at a low level by promoting p53 degradation. Nuclear export and degradation by MDM2 may contribute to the p53 nuclear exclusion phenotype. Inhibition of MDM2 expression can effectively activate p53 in most tumor types, including those without MDM2 overexpression, and may have broad anti-tumor potential.

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Acknowledgments

We are particularly grateful to Dr. Jay Hunt for use of the fluorescence microscope. We also thank Joelle Finley, Dr. James Gnarra, and Dr. Om Prakash for providing cell lines, and Dr. Ronald Luftig for critical reading of the manuscript. This work was supported by funding from the Stanley S. Scott Cancer Center and a grant from the American Cancer Society to J. Chen.

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Authors and Affiliations

  1. Department of Microbiology, Stanley S. Scott Cancer Center, Louisiana State University Medical Center, 1901 Perdido Street, New Orleans, LA, 70112, USA

    Lihong Chen, Wenge Lu &  Jiandong Chen

  2. Hybridon, Inc., Cambridge, Massachusetts, USA

    Sudhir Agrawal & Wenqiang Zhou

  3. Division of Clinical Pharmacology, University of Alabama at Birmingham, Birmingham, Alabama, USA

    Ruiwen Zhang

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  1. Lihong Chen
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  2. Wenge Lu
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  3. Sudhir Agrawal
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  4. Wenqiang Zhou
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Correspondence to Jiandong Chen.

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Chen, L., Lu, W., Agrawal, S. et al. Ubiquitous Induction of p53 in Tumor Cells by Antisense Inhibition of MDM2 Expression. Mol Med 5, 21–34 (1999). https://doi.org/10.1007/BF03402136

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  • DOI: https://doi.org/10.1007/BF03402136

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