title: ErbB4 activation inhibits MPP+-induced cell death in PC12-ErbB4 cells: involvement of PI3K and Erk signaling.
abstract: The neuroprotective effects of neuregulin (NRG), a polypeptide growth factor, on 1-methyl-4-phenylpyridinium ion (MPP+)-induced cell death and oxidative stress in PC12-ErbB4 cells were investigated. Treatment of PC12-ErbB4 cells with MPP+ induced cell death that was markedly attenuated by NRG. The PI3K/PKB/Akt and Ras/MapK signaling pathways probably mediate the survival effect of NRG. NRG induces prolonged activation of PKB/Akt and Erk. Moreover, inhibition of the PI3K and MEK activities prevented the NRG-induced survival effect. Overexpression of constitutively active PI3K or H-Ras (12V) inhibited MPP+-mediated cell death. In addition, MPP+- mediated reactive oxygen species (ROS) elevation was also inhibited by NRG. The effect of NRG on ROS levels was blocked by PI3K and MEK inhibitors, indicating that both signaling pathways can regulate the toxic ROS levels induced by MPP+. Taken together, these results indicate that in PC12-ErbB4 cells, the NRG-induced neuroprotective effect from MPP+ treatment, requires PI3K/PKB/Akt and Ras/MapK signaling networks.
authors.affiliation: Department of Neurobiochemistry, Tel-Aviv University, Ramat-Aviv, Israel.
authors.forename: Ayelet
authors.initials: A
authors.lastname: Di Segni
authors.forename: Keren
authors.initials: K
authors.lastname: Farin
authors.forename: Ronit
authors.initials: R
authors.lastname: Pinkas-Kramarski
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000037:antagonists & inhibitors* / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002867:Chromones / Q000494:pharmacology; D066246:ErbB Receptors / Q000187:drug effects / Q000502:physiology*; D005419:Flavonoids / Q000494:pharmacology; D017930:Genes, Reporter; D011905:Genes, ras; D007093:Imidazoles / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000502:physiology*; D009025:Morpholines / Q000494:pharmacology; D020890:Neuregulin-1 / Q000494:pharmacology*; D016716:PC12 Cells / Q000187:drug effects / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000009:adverse effects / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000502:physiology; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D066247:Receptor, ErbB-4; D011993:Recombinant Fusion Proteins / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014162:Transfection
chemical_list: D002867:Chromones; D005419:Flavonoids; D007093:Imidazoles; D009025:Morpholines; D020890:Neuregulin-1; D011725:Pyridines; D017382:Reactive Oxygen Species; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; C117467:neuregulin beta; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; C587691:Erbb4 protein, rat; D066247:Receptor, ErbB-4; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D016283:Proto-Oncogene Proteins p21(ras); C093642:SB 203580; D015655:1-Methyl-4-phenylpyridinium; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one