Selective inhibition of beta-F1-ATPase mRNA translation in human tumours.
Down-regulation of beta-F1-ATPase (the catalytic subunit of the mitochondrial H+-ATP synthase) is a hallmark of many human tumours. The expression level of beta-F1-ATPase provides a marker of the prognosis of cancer patients, as well as of the tumour response to chemotherapy. However, the mechanisms that participate in down-regulating its expression in human tumours remain unknown. In the present study, we have investigated the expression of beta-F1-ATPase mRNA (termed beta-mRNA) in breast, colon and lung adenocarcinomas and squamous carcinomas of the lung. Despite the down-regulation of the protein, tumour beta-mRNA levels remained either unchanged (breast and lung adenocarcinomas) or significantly increased (colon and squamous lung carcinomas) when compared with paired normal tissues, suggesting a specific translation-masking event for beta-mRNA in human cancer. Consistently, we show using cell-free translation assays that a large fraction (approximately 70%) of protein extracts derived from breast and lung adenocarcinomas specifically repress the translation of beta-mRNA. We show that the 3'UTR (3' untranslated region) of human beta-mRNA is a relevant cis-acting element required for efficient translation of the transcript. However, an RNA chimaera bearing the 3'UTR of human beta-mRNA does not recapitulate the inhibitory effect of tumour extracts on beta-mRNA translation. Overall, the findings of the present study support the hypothesis that down-regulation of the bioenergetic activity of mitochondria in human tumours is exerted by translation silencing of beta-mRNA.
Willers
Imke M
IM
Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Universidad Autónoma de Madrid, 28049 Madrid, Spain.
Isidoro
Antonio
A
Ortega
Alvaro D
AD
Fernández
Pedro L
PL
Cuezva
José M
JM
D020413:3' Untranslated Regions / Q000235:genetics; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D003110:Colonic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D025261:Mitochondrial Proton-Translocating ATPases / Q000235:genetics* / Q000378:metabolism; D009367:Neoplasm Staging; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D014176:Protein Biosynthesis / Q000187:drug effects / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014020:Tissue Extracts / Q000494:pharmacology
D020413:3' Untranslated Regions; C506526:ATP5F1B protein, human; D012333:RNA, Messenger; D014020:Tissue Extracts; D025261:Mitochondrial Proton-Translocating ATPases