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Stabilization of E2F1 protein by MDM2 through the E2F1 ubiquitination pathway

Oncogene volume 24, pages 7238–7247 (2005)Cite this article

Abstract

Although previous studies suggested that the tumorigenicity of mouse double minute 2 (MDM2) was due to its negative regulation of p53, the p53-independent interactions may be equally as important. During recent studies utilizing MDM2 inhibitors, we noted that E2F transcription factor 1 (E2F1) was downregulated upon inhibition of MDM2, regardless of the p53 status of the cancer. The present study investigated the mechanisms responsible for the MDM2-mediated increase in E2F1 expression. MDM2 prolongs the half-life of the E2F1 protein by inhibiting its ubiquitination. MDM2 displaces SCFSKP2, the E2F1 E3 ligase. Direct binding between MDM2 and E2F1 is necessary for the negative effects of MDM2 on E2F1 ubiquitination, and deletion of the MDM2 nuclear localization signal does not result in loss of the ability to increase the E2F1 protein level. The downregulation of E2F1 upon MDM2 inhibition was not due to either pRB or p14Arf. In addition, E2F1 was responsible for at least part of the inhibition of cell proliferation induced by MDM2 knockdown. In conclusion, the present study provides evidence that stabilization of the E2F1 protein is likely another p53-independent component of MDM2-mediated tumorigenesis. More knowledge about the MDM2–E2F1 interaction may be helpful in developing novel anticancer therapies.

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Abbreviations

MDM2:

mouse double minute 2

Oligo:

oligonucleotides

AS:

antisense oligonucleotide

ASM:

mismatch control oligonucleotide

E2F1:

E2F transcription factor 1

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Acknowledgements

We thank Dr Jian-He Wu for excellent technical assistance and Drs Xinbin Chen and Robert B Diasio for helpful discussions. HW was partly supported by funds for the Cancer Pharmacology Laboratory from the UAB Comprehensive Cancer Center. This work was supported by grants from the National Institutes of Health/National Cancer Institute (to RZ, Grant number CA 80698 and CA 112029). ZZ was supported in part by a post-doctoral fellowship from the USA Department of Defense Prostate Cancer Research Program (Grant number W81XWH-04-1-0845).

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology and Division of Clinical Pharmacology, University of Alabama at Birmingham, Birmingham, 35294, AL, USA

    Zhuo Zhang, Hui Wang, Mao Li, Elizabeth R Rayburn & Ruiwen Zhang

  2. Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, 35294, AL, USA

    Hui Wang & Ruiwen Zhang

  3. Hybridon, Inc., Cambridge, 02139, MA, USA

    Sudhir Agrawal

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  1. Zhuo Zhang
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Correspondence to Ruiwen Zhang.

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Zhang, Z., Wang, H., Li, M. et al. Stabilization of E2F1 protein by MDM2 through the E2F1 ubiquitination pathway. Oncogene 24, 7238–7247 (2005). https://doi.org/10.1038/sj.onc.1208814

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