Journal
BIOCHEMICAL JOURNAL
Volume 426, Issue -, Pages 319-326Publisher
PORTLAND PRESS LTD
DOI: 10.1042/BJ20091570
Keywords
cancer; H+-ATP synthase; mitochondrion; oxidative phosphorylation; regulation of gene expression; translation
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Funding
- Ministerio de Educacion y Ciencia [BFU2007-65253]
- Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBFRFR)
- Fondo de Investigacion Sanitaria [PI080274]
- ISCIII, Madrid and Camunidad de Madrid [S-GEN-0269]
- Fundacion Ramon Areces
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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 (similar to 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.
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