Role of two upstream open reading frames in the translational control of oncogene mdm2

Cheryl Y. Brown, Gregory J. Mize, Mario Pineda, Donna L. George, David R. Morris*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

89 Scopus citations

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 mRNA was loaded with ribosomes inefficiently 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.

Original languageEnglish (US)
Pages (from-to)5631-5637
Number of pages7
JournalOncogene
Volume18
Issue number41
DOIs
StatePublished - Oct 7 1999

Keywords

  • Messenger RNA
  • Neoplasms
  • Oncogene
  • Polysomes
  • Translation

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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