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Mitochondrial pyrimidine nucleotide carrier (PNC1) regulates mitochondrial biogenesis and the invasive phenotype of cancer cells

Oncogene volume 29, pages 3964–3976 (2010)Cite this article

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Abstract

The insulin-like growth factor (IGF-I) signalling pathway is essential for metabolism, cell growth and survival. It induces expression of the mitochondrial pyrimidine nucleotide carrier 1 (PNC1) in transformed cells, but the consequences of this for cell phenotype are unknown. Here we show that PNC1 is necessary to maintain mitochondrial function by controlling mitochondrial DNA replication and the ratio of transcription of mitochondrial genes relative to nuclear genes. PNC1 suppression causes reduced oxidative phosphorylation and leakage of reactive oxygen species (ROS), which activates the AMPK-PGC1α signalling pathway and promotes mitochondrial biogenesis. Overexpression of PNC1 suppresses mitochondrial biogenesis. Suppression of PNC1 causes a profound ROS-dependent epithelial–mesenchymal transition (EMT), whereas overexpression of PNC1 suppresses both basal EMT and induction of EMT by TGF-β. Overall, our findings indicate that PNC1 is essential for mitochondria maintenance and suggest that its induction by IGF-I facilitates cell growth whereas protecting cells from an ROS-promoted differentiation programme that arises from mitochondrial dysfunction.

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Acknowledgements

We thank Kurt Tidmore for assistance with illustrations and to our colleagues in the Cell Biology Laboratory for helpful discussions. This work was funded by Science Foundation Ireland and the Health Research Board.

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Authors and Affiliations

  1. Department of Biochemistry, Cell Biology Laboratory, BioSciences Institute, University College Cork, Cark, Ireland

    C Favre, M Leahy & R O'Connor

  2. Department of Biochemistry, Laboratory of Biophysics and Bioanalysis, University College Cork, Cork, Ireland

    A Zhdanov & D Papkovsky

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  1. C Favre
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  2. A Zhdanov
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  3. M Leahy
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  4. D Papkovsky
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  5. R O'Connor
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Correspondence to R O'Connor.

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Favre, C., Zhdanov, A., Leahy, M. et al. Mitochondrial pyrimidine nucleotide carrier (PNC1) regulates mitochondrial biogenesis and the invasive phenotype of cancer cells. Oncogene 29, 3964–3976 (2010). https://doi.org/10.1038/onc.2010.146

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