Translational enhancement of mdm2 oncogene expression in human tumor cells containing a stabilized wild-type p53 protein.
The mdm2 oncogene has transforming potential that is activated by overexpression. We previously reported the identification of human choriocarcinoma cell lines that have very high levels of mdm2 proteins as well as elevated levels of a stabilized wild-type p53 protein. Importantly, this mdm2 overexpression resulted from enhanced translation of mdm2 mRNA, a mechanism that had not previously been implicated in mdm2 expression control. The focus of this study was to investigate the breadth of enhanced translation of mdm2 mRNA in human cancers and to elucidate the basis for this translational activation. Here we present evidence that translational enhancement of mdm2 expression occurs in a variety of human tumor cells. Most of these samples also have high levels of wild-type p53 protein. However, there is no evidence for concomitant overexpression of the p53 target genes p21/waf1 and gadd45. Additionally, we demonstrate that the translational enhancement of mdm2 involves a preferential increase in mdm2 transcription that is initiated from the internal p53-responsive promoter region of this gene. The particular mdm2 transcripts that are generated contain a distinct 5' untranslated region and exhibit a significantly enhanced translational efficiency. These data provide a quantitative explanation for the overexpression of mdm2 proteins in this class of human tumors.
Landers
J E
JE
Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia 19104-6069, USA.
Cassel
S L
SL
George
D L
DL
D001483:Base Sequence; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D018076:DNA, Complementary / Q000032:analysis; D016158:Genes, p53 / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008545:Melanoma / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins; D016133:Polymerase Chain Reaction; D014176:Protein Biosynthesis; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D012313:RNA / Q000032:analysis; D012333:RNA, Messenger / Q000378:metabolism*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D000097642:GADD45 Proteins
D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D018076:DNA, Complementary; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D051736:Proto-Oncogene Proteins c-mdm2; D012313:RNA; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D000097642:GADD45 Proteins; C493956:CDKN1A protein, human; C497206:MDM2 protein, human