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
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.
DOI of Published Version
J Biol Chem. 2004 Feb 6;279(6):4877-86. Epub 2003 Nov 10. Link to article on publisher's site
The Journal of biological chemistry
Steinman HA, Burstein E, Lengner CJ, Gosselin JR, Pihan GA, Duckett CS, Jones SN. (2003). An alternative splice form of Mdm2 induces p53-independent cell growth and tumorigenesis. Morningside Graduate School of Biomedical Sciences Student Publications. https://doi.org/10.1074/jbc.M305966200. Retrieved from https://escholarship.umassmed.edu/gsbs_sp/1197