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

• Published in: The Journal of biological chemistry Vol. 279; no. 6; pp. 4877 - 4886
• Main Authors: Steinman, Heather A., Burstein, Ezra, Lengner, Christopher, Gosselin, Joseph, Pihan, German, Duckett, Colin S., Jones, Stephen N.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06-02-2004; American Society for Biochemistry and Molecular Biology
• Subjects: Alternative Splicing; Amino Acid Sequence; Animals; Apoptosis; Base Sequence; Cell Division; DNA, Complementary - genetics; Humans; Mdm2 protein; Mice; Mice, Transgenic; Molecular Sequence Data; NIH 3T3 Cells; Nuclear Proteins; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-mdm2; Sarcoma, Experimental - etiology; Sarcoma, Experimental - genetics; Sarcoma, Experimental - metabolism; Sequence Homology, Amino Acid; Transfection; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M305966200

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.