Abstract
Overexpression of oncoprotein MDM2 has been found in a significant number of human soft tissue tumors. In a subset of these tumors, overexpression is a result of enhanced translation of mdm2 mRNA. There are two transcripts from the mdm2 gene that differ only in their 5′ leaders: a long form (L-mdm2) and a short form (S-mdm2) that arise from the use of different promoters. L-mdm2 mRNA contains two upstream open reading frames (uORFs) and this mRNA was loaded with ribosomes inefficiently in comparison with S-mdm2. The 5′ leader of L-mdm2 was sufficient to transfer translational repression to a reporter gene and the two uORFs acted synergistically to achieve full suppression. In contrast, the 5′ leader of S-mdm2 allowed efficient translation of an attached reporter gene in the tumor cells. These results are consistent with a model in which overexpression of MDM2 in certain tumors results from a change in mRNA structure due to a switch in promoter usage.
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Acknowledgements
This research was supported in part by research grants from the National Institutes of Health (CA39053 to DR Morris and CA66741 to DL George).
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Brown, C., Mize, G., Pineda, M. et al. Role of two upstream open reading frames in the translational control of oncogene mdm2. Oncogene 18, 5631–5637 (1999). https://doi.org/10.1038/sj.onc.1202949
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DOI: https://doi.org/10.1038/sj.onc.1202949
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