2024-03-28T18:45:21Zhttps://gredos.usal.es/oai/requestoai:gredos.usal.es:10366/177152022-02-07T14:33:22Zcom_10366_3966com_10366_3947com_10366_3946com_10366_3823col_10366_3967
Inhibition of PTEN by peroxynitrite activates the phosphoinositide-3-kinase/Akt neuroprotective signaling pathway
Delgado Esteban, María
Martín Zanca, Dionisio
Andrés Martín, Laura
Almeida Parra, Ángeles
Bolaños Hernández, Juan Pedro
Neuroprotección
Akt
PTEN
Apoptosis
Óxido nítrico
Peroxinitrito
Anti-apoptotic
Neuroprotection
Peroxynitrite
PI3K
El derivado del óxido nítrico, peroxinitrito, activa una cascada de señalización de supervivencia en neuronas. El mecanismo implica la oxidación de la fosfatasa PTEN, que permite incrementar la forma fosforilada (neuroprotectora) de akt.
Peroxynitrite is usually considered as a neurotoxic nitric oxidederivative. However, an increasing body of evidence suggests that, at low concentrations, peroxynitrite affords transient cytoprotection, both in vitro and in vivo. Here, we addressed the signaling mechanism responsible for this effect, and found that rat cortical neurons in primary culture acutely exposed to peroxynitrite (0.1 mmol/L) rapidly elicited Akt-Ser473 phosphorylation. Inhibition of phosphoinositide-3-kinase (PI3K)/Akt pathway with wortmannin or Akt small hairpin RNA (shRNA) abolished the ability of peroxynitrite to prevent etoposide-induced apoptotic death. Endogenous peroxynitrite formation by short-term incubation of neurons with glutamate stimulated Akt-Ser473 phosphorylation, whereas Akt shRNA enhanced the vulnerability of neurons against glutamate. We further show that Akt-Ser473 phosphorylation was consequence of the oxidizing, but not the nitrating properties of peroxynitrite. Peroxynitrite failed to nitrate or phosphorylate neurotrophin tyrosine kinase receptors (Trks), and it did not modify the ability of brain-derived neurotrophic factor (BDNF), to phosphorylate its cognate receptor, TrkB; however, peroxynitrite enhanced BDNF-mediated Akt-Ser473 phosphorylation. Finally, we found that peroxynitrite-stimulated Akt-Ser473 phosphorylation was associated with an increased proportion of oxidized phosphoinositide phosphatase, PTEN, in neurons. Moreover, peroxynitrite prevented the increase of apoptotic neuronal death caused by over-expression of PTEN. Thus, peroxynitrite exerts neuroprotection by inhibiting PTEN, hence activating the anti-apoptotic PI3K/Akt pathway in primary neurons.
2009-10-07T09:10:29Z
2009-10-07T09:10:29Z
2009-10-07T09:10:29Z
2007
info:eu-repo/semantics/article
info:eu-repo/semantics/article
Delgado Esteban, M., Martín Zanca, D., Andrés Martín, L., Almeida Parra, A., y Bolaños Hernández, J.P. (2007). Inhibition of PTEN by peroxynitrite activates the phosphoinositide-3-kinase/Akt neuroprotective signaling pathway. "Journal of Neurochemistry", 102, 194-205.
http://hdl.handle.net/10366/17715
http://hdl.handle.net/10366/17715
eng
Adobe Acrobat
https://creativecommons.org/licenses/by-nc-nd/3.0/
info:eu-repo/semantics/openAccess
Attribution-NonCommercial-NoDerivs 3.0 Unported
Blackwell Publishing Ltd. (Oxford, Gran Bretaña)