The Insulin-like Growth Factor-I–mTOR Signaling Pathway Induces the Mitochondrial Pyrimidine Nucleotide Carrier to Promote Cell Growth
Copyright policy )The Insulin-like Growth Factor-I–mTOR Signaling Pathway Induces the Mitochondrial Pyrimidine Nucleotide Carrier to Promote Cell Growth
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.
- Heidelberg University Germany
- National Research Council Sri Lanka
- National Research Council Italy
- Pathologisches Institut Germany
- University of Bari Aldo Moro Italy
Molecular Sequence Data, Mitochondrial Proteins, Mice, Cell Line, Tumor, Animals, Humans, Insulin, Amino Acid Sequence, Insulin-Like Growth Factor I, RNA, Small Interfering, Cell Line, Transformed, Cell Proliferation, Cell Size, RECEPTOR, IDENTIFICATION, TRANSPORTER, Biological Transport, Fibroblasts, CANCER, GENE, Mitochondria, Enzyme Activation, Gene Expression Regulation, Neoplastic, Nucleotide Transport Proteins, Protein Kinases
Molecular Sequence Data, Mitochondrial Proteins, Mice, Cell Line, Tumor, Animals, Humans, Insulin, Amino Acid Sequence, Insulin-Like Growth Factor I, RNA, Small Interfering, Cell Line, Transformed, Cell Proliferation, Cell Size, RECEPTOR, IDENTIFICATION, TRANSPORTER, Biological Transport, Fibroblasts, CANCER, GENE, Mitochondria, Enzyme Activation, Gene Expression Regulation, Neoplastic, Nucleotide Transport Proteins, Protein Kinases
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