RT Journal Article
T1 Regulation of heme oxygenase-1 gene expression through the phosphatidylinositol 3-kinase/PKC-zeta pathway and Sp1
A1 Rojo, Ana
A1 Salinas, Marta
A1 Salazar Roa, María
A1 Takahashi, Shigeru
A1 Suske, Guntram
A1 Calvo, Victor
A1 Sagarra, María Rosa de
A1 Cuadrado, Antonio
AB 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.
PB Elsevier
SN 0891-5849
YR 2006
FD 2006
LK https://hdl.handle.net/20.500.14352/97400
UL https://hdl.handle.net/20.500.14352/97400
LA eng
NO Rojo, Ana I., et al. «Regulation of Heme Oxygenase-1 Gene Expression through the Phosphatidylinositol 3-Kinase/PKC-ζ Pathway and Sp1». Free Radical Biology and Medicine, vol. 41, n.o 2, julio de 2006, pp. 247-61. https://doi.org/10.1016/j.freeradbiomed.2006.04.002.
NO Ministerio de Educación (España)
NO Comunidad de Madrid
NO Instituto de Salud Carlos III
DS Docta Complutense
RD 12 abr 2025