Neuregulin rescues PC12-ErbB4 cells from cell death induced by H(2)O(2). Regulation of reactive oxygen species levels by phosphatidylinositol 3-kinase.
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-alpha treatment. In the present study we show that NRG induces a significant protective effect from H(2)O(2)-induced death. This effect of NRG is mediated by the phosphatidylinositol 3-kinase (PI3K)-signaling pathway since NRG failed to rescue cells from H(2)O(2) 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 H(2)O(2), and protein kinase B/AKT activation is inhibited by LY294002. In addition, our results demonstrate that reactive oxygen species (ROS) elevation induced by H(2)O(2) is inhibited by NRG. LY294002, which blocks NRG-mediated rescue, increases ROS levels. Moreover, both H(2)O(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.
Goldshmit
Y
Y
Department of Neurobiochemistry. Tel-Aviv University, Ramat-Aviv, 69978, Israel.
Erlich
S
S
Pinkas-Kramarski
R
R
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D009025:Morpholines / Q000494:pharmacology; D020880:Neuregulins / Q000502:physiology*; D016716:PC12 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051381:Rats; D017382:Reactive Oxygen Species; D066247:Receptor, ErbB-4; D015398:Signal Transduction
D002867:Chromones; D004791:Enzyme Inhibitors; D066246:ErbB Receptors; D006861:Hydrogen Peroxide; D009025:Morpholines; D020880:Neuregulins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017382:Reactive Oxygen Species; D066247:Receptor, ErbB-4; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C587691:Erbb4 protein, rat