An Alternative Splice Form of Mdm2 Induces p53-independent Cell Growth and Tumorigenesis

Heather A. Steinman, Ezra Burstein, Christopher Lengner, Joseph Gosselin, German Pihan, Colin S. Duckett, Stephen N. Jones

Research output: Contribution to journalArticle

84 Scopus citations

Abstract

The Mdm2 gene is amplified in approximately one-third of human sarcomas and overexpressed in a variety of other human cancers. Mdm2 functions as an oncoprotein, in part, by acting as a negative regulator of the p53 tumor suppressor protein. Multiple spliced forms of Mdm2 transcripts have been observed in human tumors; however, the contribution of these variant transcripts to tumorigenesis is unknown. In this report, we isolate alternative splice forms of Mdm2 transcripts from sarcomas that spontaneously arise in Mdm2-overexpressing mice, including Mdm2-b, the splice form most commonly observed in human cancers. Transduction of Mdm2-b into a variety of cell types reveals that Mdm2-b promotes p53-independent cell growth, inhibits apoptosis, and up-regulates the RelA subunit of NFκB. Furthermore, expression of Mdm2-b induces tumor formation in transgenic mice. These results identify a p53-independent role for Mdm2 and determine that an alternate spliced form of Mdm2 can contribute to formation of cancer via a p53-independent mechanism. These findings also provide a rationale for the poorer prognosis of those patients presenting with tumors harboring multiple Mdm2 transcripts.

Original languageEnglish (US)
Pages (from-to)4877-4886
Number of pages10
JournalJournal of Biological Chemistry
Volume279
Issue number6
DOIs
StatePublished - Feb 6 2004

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Steinman, H. A., Burstein, E., Lengner, C., Gosselin, J., Pihan, G., Duckett, C. S., & Jones, S. N. (2004). An Alternative Splice Form of Mdm2 Induces p53-independent Cell Growth and Tumorigenesis. Journal of Biological Chemistry, 279(6), 4877-4886. https://doi.org/10.1074/jbc.M305966200