Role of two upstream open reading frames in the translational control of oncogene mdm2.
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.
Brown
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Department of Biochemistry, University of Washington, Seattle, Washington, WA 98195-7350, USA.
Mize
G J
GJ
Pineda
M
M
George
D L
DL
Morris
D R
DR
D020121:5' Untranslated Regions / Q000235:genetics; D002478:Cells, Cultured; D002822:Choriocarcinoma / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006367:HeLa Cells; D019382:Human Growth Hormone / Q000494:pharmacology; D006801:Humans; D008168:Lung / Q000166:cytology; D009687:Nuclear Proteins; D009857:Oncogenes; D016366:Open Reading Frames; D011401:Promoter Regions, Genetic; D014176:Protein Biosynthesis; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D051736:Proto-Oncogene Proteins c-mdm2; D012333:RNA, Messenger / Q000235:genetics*; D012270:Ribosomes / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000378:metabolism; D014594:Uterine Neoplasms / Q000473:pathology
D020121:5' Untranslated Regions; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D019382:Human Growth Hormone; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2