TY - JOUR
T1 - Neuregulin rescues PC12-ErbB4 cells from cell death induced by H 2O2
T2 - Regulation of reactive oxygen species levels by phosphatidylinositol 3-kinase
AU - Goldshmit, Yona
AU - Erlich, Shlomit
AU - Pinkas-Kramarski, Ronit
PY - 2001/12/7
Y1 - 2001/12/7
N2 - Neuregulins (NRGs), a large family of transmembrane polypeptide growth factors, mediate various cellular responses depending on the cell type and receptor expression. We previously showed that NRG mediates survival of PC12-ErbB4 cells from apoptosis induced by serum deprivation or tumor necrosis factor-α treatment. In the present study we show that NRG induces a significant protective effect from H2O2-induced death. This effect of NRG is mediated by the phosphatidylinositol 3-kinase (PI3K)-signaling pathway since NRG failed to rescue cells from H 2O2 insult in the presence of the PI3K inhibitor, LY294002. Furthermore, the downstream effector of PI3K, protein kinase B/AKT, is activated by NRG in the presence of H2O2, and protein kinase B/AKT activation is inhibited by LY294002. In addition, our results demonstrate that reactive oxygen species (ROS) elevation induced by H 2O2 is inhibited by NRG. LY294002, which blocks NRG-mediated rescue, increases ROS levels. Moreover, both H2O 2-induced ROS elevation and cell death are reduced by expression of activated PI3K. These results suggest that PI3K-dependent pathways may regulate toxic levels of ROS generated by oxidative stress.
AB - Neuregulins (NRGs), a large family of transmembrane polypeptide growth factors, mediate various cellular responses depending on the cell type and receptor expression. We previously showed that NRG mediates survival of PC12-ErbB4 cells from apoptosis induced by serum deprivation or tumor necrosis factor-α treatment. In the present study we show that NRG induces a significant protective effect from H2O2-induced death. This effect of NRG is mediated by the phosphatidylinositol 3-kinase (PI3K)-signaling pathway since NRG failed to rescue cells from H 2O2 insult in the presence of the PI3K inhibitor, LY294002. Furthermore, the downstream effector of PI3K, protein kinase B/AKT, is activated by NRG in the presence of H2O2, and protein kinase B/AKT activation is inhibited by LY294002. In addition, our results demonstrate that reactive oxygen species (ROS) elevation induced by H 2O2 is inhibited by NRG. LY294002, which blocks NRG-mediated rescue, increases ROS levels. Moreover, both H2O 2-induced ROS elevation and cell death are reduced by expression of activated PI3K. These results suggest that PI3K-dependent pathways may regulate toxic levels of ROS generated by oxidative stress.
UR - http://www.scopus.com/inward/record.url?scp=0035824526&partnerID=8YFLogxK
U2 - 10.1074/jbc.M105637200
DO - 10.1074/jbc.M105637200
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C2 - 11590144
AN - SCOPUS:0035824526
SN - 0021-9258
VL - 276
SP - 46379
EP - 46385
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 49
ER -