The insulin-like growth factor-I-mTOR signaling pathway induces the mitochondrial pyrimidine nucleotide carrier to promote cell growth.

TitleThe insulin-like growth factor-I-mTOR signaling pathway induces the mitochondrial pyrimidine nucleotide carrier to promote cell growth.
Publication TypeJournal Article
Year of Publication2007
AuthorsFloyd, S, Favre, C, Lasorsa, FM, Leahy, M, Trigiante, G, Stroebel, P, Marx, A, Loughran, G, O'Callaghan, K, Marobbio, CMT, Slotboom, DJ, Kunji, ERS, Palmieri, F, O'Connor, R
JournalMol Biol Cell
Volume18
Issue9
Pagination3545-55
Date Published2007 Sep
ISSN1059-1524
KeywordsAmino Acid Sequence, Animals, Biological Transport, Cell Line, Transformed, Cell Line, Tumor, Cell Proliferation, Cell Size, Enzyme Activation, Fibroblasts, Gene Expression Regulation, Neoplastic, Humans, Insulin, Insulin-Like Growth Factor I, Mice, Mitochondria, Mitochondrial Proteins, Molecular Sequence Data, Nucleotide Transport Proteins, Protein Kinases, Reactive Oxygen Species, Receptor, IGF Type 1, RNA, Small Interfering, Signal Transduction, TOR Serine-Threonine Kinases, Uridine Triphosphate
Abstract

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.

DOI10.1091/mbc.e06-12-1109
Alternate JournalMol. Biol. Cell
Citation Key10.1091/mbc.e06-12-1109
PubMed ID17596519
PubMed Central IDPMC1951771
Grant ListMC_U105663139 / / Medical Research Council / United Kingdom