A conserved mechanism for controlling the translation of beta-F1-ATPase mRNA between the fetal liver and cancer cells.
To characterize the mechanisms governing the biogenesis of mitochondria in cancer, we studied the mitochondrial phenotype and the mechanisms controlling the expression of the beta subunit of the mitochondrial H(+)-ATP synthase (beta-F1-ATPase) gene in the rat FAO and AS30D hepatomas. When compared with normal adult rat liver, the relative cellular content of the mitochondrial beta-F1-ATPase and glutamate dehydrogenase, as well as of mitochondrial DNA, was severely reduced in both cell lines. A paradoxical increase in the cellular abundance of beta-F1-ATPase mRNA was observed in cancer cells. Run-on transcription assays and the estimation of mRNA half-lives revealed that the increased abundance of beta-F1-ATPase mRNA results from the stabilization of the transcript in cancer. In vitro translation assays revealed a specific inhibition of the synthesis of the beta-precursor when translation reactions were carried out in the presence of extracts derived from cancer cells. The inhibitory effect was recapitulated using an RNA chimera that contained the 3'-untranslated region of beta-F1-ATPase mRNA. Hepatoma extracts also contained an increased activity of the developmentally regulated translation-inhibitory proteins that bind the 3'-untranslated region of beta-F1-ATPase mRNA. The results indicate that the expression of this gene in hepatoma cells is controlled by the same mechanisms that regulate its expression in the liver during fetal development.
de Heredia
M L
ML
Departamento de Biología Molecular, Centro de Biología Molecular "Severo Ochoa," Universidad Autónoma de Madrid, 28049 Madrid, Spain.
Izquierdo
J M
JM
Cuezva
J M
JM
D020413:3' Untranslated Regions; D000818:Animals; D004272:DNA, Mitochondrial / Q000032:analysis; D005260:Female; D005333:Fetus; D015971:Gene Expression Regulation, Enzymologic; D008099:Liver / Q000201:enzymology*; D008114:Liver Neoplasms, Experimental / Q000201:enzymology*; D008930:Mitochondria, Liver / Q000201:enzymology; D010085:Oxidative Phosphorylation; D014176:Protein Biosynthesis; D006180:Proton-Translocating ATPases / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014158:Transcription, Genetic
D020413:3' Untranslated Regions; D004272:DNA, Mitochondrial; D012333:RNA, Messenger; D006180:Proton-Translocating ATPases