Stabilization of E2F1 protein by MDM2 through the E2F1 ubiquitination pathway View Full Text


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Article Info

DATE

2005-09-19

AUTHORS

Zhuo Zhang, Hui Wang, Mao Li, Elizabeth R Rayburn, Sudhir Agrawal, Ruiwen Zhang

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. More... »

PAGES

7238-7247

References to SciGraph publications

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  • 2003-07. The yin and yang of E2F-1: balancing life and death in NATURE CELL BIOLOGY
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  • 1995-11. Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53 in NATURE
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  • 2004-04-29. Up-regulation of transcriptional factor E2F1 in papillary and anaplastic thyroid cancers in JOURNAL OF HUMAN GENETICS
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/sj.onc.1208814

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    http://dx.doi.org/10.1038/sj.onc.1208814

    DIMENSIONS

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    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/16170383


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