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Vol. 18, Issue 9, 3545-3555, September 2007

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The Insulin-like Growth Factor-I–mTOR Signaling Pathway Induces the Mitochondrial Pyrimidine Nucleotide Carrier to Promote Cell Growth

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

*Cell Biology Laboratory, Department of Biochemistry, BioSciences Institute, National University of Ireland, Cork, Ireland; Department of Pharmaco-Biology, Laboratory of Biochemistry and Molecular Biology, University of Bari, and Consiglio Nazionale delle Ricerche Institute of Biomembranes and Bioenergetics, 70125 Bari, Italy; Institute of Pathology, University Hospital Mannheim, University of Heidelberg, D68135 Mannheim, Germany; and Medical Research Council, Dunn Human Nutrition Unit, Cambridge CB2 2XY, United Kingdom

Submitted December 15, 2006; Revised June 11, 2007; Accepted June 14, 2007
Monitoring Editor: Carl-Henrik Heldin

The insulin/insulin-like growth factor (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 PI-3 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 reduced PNC1 expression have reduced mitochondrial UTP levels, but while mitochondrial membrane potential and cellular ATP are not altered, cellular ROS levels are increased. 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.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

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