Hypoxia induces an autocrine‐paracrine survival pathway via platelet‐derived growth factor (PDGF)‐B/PDGF‐β receptor/phosphatidylinositol 3‐kinase/Akt signaling in RN46A neuronal cells
- 3 July 2003
- journal article
- Published by Wiley in The FASEB Journal
- Vol. 17 (12), 1709-1711
- https://doi.org/10.1096/fj.02-1111fje
Abstract
In neurons, hypoxia activates intracellular death-related pathways, yet the antiapoptotic mechanisms triggered by hypoxia remain unclear. In RN46A neuronal cells, minimum media growth conditions induced cell death as early as 12 h after the cells were placed in these conditions (i.e., after removal of B-27 supplement). However, apoptosis occurred in hypoxia (1% O2) only after 48 h, and in fact hypoxia reduced the apoptosis associated with trophic factor withdrawal. Furthermore, hypoxia induced time-dependent increases in expression of platelet-derived growth factor (PDGF) B mRNA and protein, as well as PDGF-beta receptor phosphorylation. Although exogenous PDGF-BB induced only transient Akt activation, hypoxia triggered persistent activation of Akt for up to 24 h. Inhibition of phosphatidylinositol 3-kinase (PI3K) or of PDGF-beta receptor phosphorylation abrogated both hypoxia-induced and exogenous PDGF-BB-induced Akt phosphorylation, and it completely abolished hypoxia-induced protection from media supplement deprivation, which suggests that the long-lasting activation of Akt during hypoxia and the prosurvival induction were due to endogenously generated PDGF-BB. Furthermore, these inhibitors decreased hypoxia-inducible factor 1alpha (HIF-1alpha) DNA binding, which suggests that the PDGF/PDGF-beta receptor/Akt pathway induces downstream HIF-1alpha gene transcription. We conclude that in RN46A neuronal cells, hypoxia activates an autocrine-paracrine antiapoptotic mechanism that involves up-regulation of PDGF-B and PDGF-beta receptor-dependent activation of the PI3K/Akt signaling pathway to induce downstream transcription of survival genes.Keywords
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