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Your search keyword '"Patriarca E"' showing total 5 results
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5. A novel autoregulatory loop between the Gcn2-Atf4 pathway and L-Proline metabolism controls stem cell identity

Author

G Di Napoli, Gilda Cobellis, Ombretta Guardiola, Annalisa Fico, Eduardo J. Patriarca, Federica Cermola, Cristina D'Aniello, Laura Casalino, Rosarita Tatè, D De Cesare, Gabriella Minchiotti, D'Aniello, C, Fico, A, Casalino, L, Guardiola, O, Di Napoli, G, Cermola, F, De Cesare, D, Tatè, R, Cobellis, G, Patriarca, E J, and Minchiotti, G

Subjects
L-Proroline, Proline, Protein Serine-Threonine Kinases, Protein-Serine-Threonine Kinase, Activating Transcription Factor 4, Biology, Mice, Embryonic Stem Cell, Stress, Physiological, Animals, Induced pluripotent stem cell, Molecular Biology, Embryonic Stem Cells, Feedback, Physiological, chemistry.chemical_classification, Original Paper, Animal, Cell growth, Cell Biology, Embryonic stem cell, Amino acid, chemistry, Biochemistry, embryonic structures, Erratum, Signal transduction, Stem cell, Starvation response, Signal Transduction
Abstract

Increasing evidence indicates that metabolism is implicated in the control of stem cell identity. Here, we demonstrate that embryonic stem cell (ESC) behaviour relies on a feedback loop that involves the non-essential amino acid L-Proline (L-Pro) in the modulation of the Gcn2-Eif2?-Atf4 amino acid starvation response (AAR) pathway that in turn regulates L-Pro biosynthesis. This regulatory loop generates a highly specific intrinsic shortage of L-Pro that restricts proliferation of tightly packed domed-like ESC colonies and safeguards ESC identity. Indeed, alleviation of this nutrient stress condition by exogenously provided L-Pro induces proliferation and modifies the ESC phenotypic and molecular identity towards that of mesenchymal-like, invasive pluripotent stem cells. Either pharmacological inhibition of the prolyl-tRNA synthetase by halofuginone or forced expression of Atf4 antagonises the effects of exogenous L-Pro. Our data provide unprecedented evidence that L-Pro metabolism and the nutrient stress response are functionally integrated to maintain ESC identity.Cell Death and Differentiation advance online publication, 10 April 2015; doi:10.1038/cdd.2015.24.

Published
2015
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