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Título: | Regulation of heme oxygenase-1 gene expression through the phosphatidylinositol 3-kinase/PKC-ζ pathway and Sp1 |
Autor: | Rojo, Ana I. CSIC ORCID; Salinas, Marta; Salazar, María CSIC; Calvo, Victor CSIC ORCID; Sagarra, María Rosa de CSIC; Cuadrado, Antonio CSIC ORCID | Fecha de publicación: | 2006 | Editor: | Elsevier | Citación: | Free Radical Biology and Medicine 41(2): 247-261 (2006) | Resumen: | The molecular mechanisms involved in modulation of the antioxidant cell defence by survival signals remain largely unexplored. Here, we report a mechanistic connection between the survival signal elicited by nerve growth factor (NGF) and the antioxidant cell defence represented by heme oxygenase-1 (HO-1) at the level of a newly identified Sp1 site in the human ho1 proximal promoter. By using luciferase reporter constructs we identified a PI3K-responsive region containing a GC-box that resembled the response element for Sp1. Indeed, transfection of Sp1-deficient SL2 cells, electrophoretic mobility shift assays, the use of the GC-box binding drug mithramycin, and mutation of the GC-box provided evidence for a Sp1-like site in the PI3K-sensitive region. Then, we observed with the use of a Sp1-Gal4 chimera that PI3K regulates the transactivating capacity of Sp1. Cotransfection of active PI3K and PKC-ζ expression vectors resulted in substantial increase of Sp1 phosphorylation and in synergistic activation of both Sp1-Gal4 and endogenous Sp1. Moreover, these effects were mimicked by cotransfection of active MEK and ERK expression vectors and were blocked by the MEK inhibitor PD98059. Inhibition of HO-1 with Sn protoporphyrin IX and blockage of Sp-1-mediatied upregulation of HO-1 with mithramycin attenuated antioxidant and cytoprotective functions of NGF against hydrogen peroxide. This study elucidates how NGF contributes to protection of target cells against oxidative stress. © 2006 Elsevier Inc. All rights reserved. | URI: | http://hdl.handle.net/10261/81382 | DOI: | 10.1016/j.freeradbiomed.2006.04.002 | Identificadores: | doi: 10.1016/j.freeradbiomed.2006.04.002 issn: 0891-5849 e-issn: 1873-4596 |
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