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MBC in Press, published online ahead of print June 27, 2007
Mol. Biol. Cell 10.1091/mbc.E06-12-1109

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Submitted on December 15, 2006
Revised on June 11, 2007
Accepted on June 14, 2007

The IGF-I-mTOR Signaling Pathway Induces the Mitochondrial Pyrimidine Nucleotide Carrier to Promote Cell Growth

Suzanne Floyd,* Cedric Favre,* Francesco M. Lasorsa,{dagger} Madeline Leahy,* Giuseppe Trigiante,* Philipp Stroebel,{ddagger} Alexander Marx,{ddagger} Gary Loughran,* Katie O’Callaghan,* Carlo M.T. Marobbio,{dagger} Dirk J. Slotboom,{sect} Edmund R.S. Kunji,{sect} Ferdinando Palmieri,{dagger} and Rosemary O’Connor*

*Cell Biology Laboratory, Department of Biochemistry, BioSciences Institute, National University of Ireland, Cork, Ireland; {dagger}Department of Pharmaco-Biology, Laboratory of Biochemistry and Molecular Biology, University of Bari, and Consiglio Nazionale delle Ricerche Institute of Biomembranes and Bioenergetics, Bari, Italy; {ddagger}Institute of Pathology, University Hospital Mannheim, University of Heidelberg, Germany; {sect}Medical Research Council, Dunn Human Nutrition Unit, Cambridge CB2 2XY, United Kingdom

Monitoring Editor: Carl-Henrik Heldin

The Insulin/IGF signaling pathway to mTOR is essential for the survival and growth of normal cells and also contributes to the genesis and progression of cancer. This signaling pathway is linked with regulation of mitochondrial function, but how is incompletely understood. Here we show that IGF-I and insulin induce rapid transcription of the mitochondrial pyrimidine nucleotide carrier PNC1, which shares significant identity with the essential yeast mitochondrial carrier Rim2p. PNC1 expression is dependent on PI3-kinase and mTOR activity and is higher in transformed fibroblasts, cancer cell lines, and primary prostate cancers than in normal tissues. Overexpression of PNC1 enhances cell size, whereas suppression of PNC1 expression causes reduced cell size, and retarded cell cycle progression and proliferation. Cells with suppressed PNC1 expression have reduced mitochondrial UTP levels, but mitochondrial mass and cellular ATP are not altered. Overall the data indicate that PNC1 is a target of the IGF-I/mTOR pathway that is essential for mitochondrial activity in regulating cell growth and proliferation.

Address correspondence to: Rosemary O’Connor (r.oconnor{at}ucc.ie)




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