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

Oncogene. 1999 Oct 7;18(41):5631-7. doi: 10.1038/sj.onc.1202949.

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 5' Untranslated Regions / genetics
  • Cells, Cultured
  • Choriocarcinoma / pathology
  • Female
  • Fibroblasts / metabolism
  • Gene Expression Regulation, Neoplastic* / drug effects
  • HeLa Cells
  • Human Growth Hormone / pharmacology
  • Humans
  • Lung / cytology
  • Nuclear Proteins*
  • Oncogenes*
  • Open Reading Frames
  • Promoter Regions, Genetic
  • Protein Biosynthesis*
  • Proto-Oncogene Proteins / biosynthesis
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins c-mdm2
  • RNA, Messenger / genetics*
  • Ribosomes / metabolism
  • Tumor Cells, Cultured / metabolism
  • Uterine Neoplasms / pathology

Substances

  • 5' Untranslated Regions
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Human Growth Hormone
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2