An alternative splice form of Mdm2 induces p53-independent cell growth and tumorigenesis
Graduate School of Biomedical Sciences; Department of Pathology; Department of Cell Biology
Medical Subject Headings
*Alternative Splicing; Amino Acid Sequence; Animals; Apoptosis; Base Sequence; Cell Division; DNA, Complementary; Humans; Mice; Mice, Transgenic; Molecular Sequence Data; NIH 3T3 Cells; *Nuclear Proteins; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-mdm2; Sarcoma, Experimental; Sequence Homology, Amino Acid; Transfection; Tumor Suppressor Protein p53
Life Sciences | Medicine and Health Sciences
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 NFkappaB. 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.
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Citation: J Biol Chem. 2004 Feb 6;279(6):4877-86. Epub 2003 Nov 10. Link to article on publisher's site