Selective inhibition of beta-F1-ATPase mRNA translation in human tumours

Imke M. Willers, Antonio Isidoro, Alvaro D. Ortega, Pedro L. Fernandez, Jose M. Cuezva*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)319-326
Number of pages8
JournalBiochemical Journal
Volume426
DOIs
Publication statusPublished - 15 Mar 2010

Keywords

  • cancer
  • H+-ATP synthase
  • mitochondrion
  • oxidative phosphorylation
  • regulation of gene expression
  • translation
  • H+-ATP SYNTHASE
  • BIOENERGETIC SIGNATURE
  • BETA-SUBUNIT
  • MITOCHONDRIAL BIOGENESIS
  • GENE-EXPRESSION
  • CANCER-CELLS
  • PROTEIN
  • EFFICIENCY
  • COMPLEX
  • BREAST

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