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Lopez-Iglesias P.,La Paz Hospital Research Institute | Alcaina Y.,La Paz Hospital Research Institute | Tapia N.,Max Planck Institute for Molecular Biomedicine | Sabour D.,Max Planck Institute for Molecular Biomedicine | And 10 more authors.
Antioxidants and Redox Signaling | Year: 2015

To study the mechanisms of pluripotency induction, we compared gene expression in pluripotent embryonic germ cells (EGCs) and unipotent primordial germ cells (PGCs). Results: We found 11 genes ≥1.5-fold overexpressed in EGCs. None of the genes identified was the Yamanaka genes but instead related to glycolytic metabolism. The prospect of pluripotency induction by cell metabolism manipulation was investigated by hypoxic culturing. Hypoxia induced a glycolytic program in PGCs in detriment of mitochondrial oxidative phosphorylation. We demonstrate that hypoxia alone induces reprogramming in PGCs, giving rise to hypoxia-induced EGC-like cells (hiEGLs), which differentiate into cells of the three germ layers in vitro and contribute to the internal cell mass of the blastocyst in vivo, demonstrating pluripotency. The mechanism of hypoxia induction involves HIF1α stabilization and Oct4 deregulation. However, hiEGL cannot be passaged long term. Self-renewal capacity is not achieved by hypoxia likely due to the lack of upregulation of c-Myc and Klf4. Gene expression analysis of hypoxia signaling suggests that hiEGLs have not reached the stabilization phase of cell reprogramming. Innovation and Conclusion: Our data suggest that the two main properties of stemness, pluripotency and self-renewal, are differentially regulated in PGC reprogramming induced by hypoxia. Antioxid. Redox Signal. 22, 205-223. © 2015 Mary Ann Liebert, Inc. Source


Nunez-O'Mara A.,Research Center Cooperativa en Biociencias bio | Gerpe-Pita A.,Research Center Cooperativa en Biociencias bio | Pozo S.,Research Center Cooperativa en Biociencias bio | Carlevaris O.,Research Center Cooperativa en Biociencias bio | And 4 more authors.
Journal of Cell Science | Year: 2015

By controlling HIFα hydroxylation and stability, the prolyl hydroxylase domain (PHD)-containing proteins are essential to the maintenance of oxygen homeostasis; therefore these enzymes are tightly regulated. Small ubiquitin-like modifier (SUMO) is a 10-kDa protein readily conjugated to lysine residues of the targeted proteins in a process termed SUMOylation. In this study, we introduce SUMO conjugation as a novel regulator of PHD3 (also known as EGLN3). PHD3 SUMOylation occurs at a cluster of four lysines at the C-terminal end of the protein. Furthermore, PHD3 SUMOylation by SUMO2 or SUMO3 contributes to PHD3-mediated repression of HIF1-dependent transcriptional activity. Interestingly, PHD3-SUMO conjugation does not affect PHD3 hydroxylase activity or HIF1α stability, providing new evidence for a dual role of PHD3 in HIF1 regulation. Moreover, we show that hypoxia modulates PHD3-SUMO conjugation and that this modification inversely correlates with HIF1 activation. PHD3 SUMOylation highlights a new and additional layer of regulation that is likely required to fine-tune HIF function. © 2015. Published by The Company of Biologists Ltd. Source

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