Growth differentiation factor-15 prevents low potassium-induced cell death of cerebellar granule neurons by differential regulation of Akt and ERK pathways.
Growth differentiation factor-15 (GDF-15) is a novel member of the transforming growth factor-beta superfamily and has been shown to be induced in neurons subsequent to lesions. We have therefore begun to study its putative role in the regulation of neuron survival and apoptosis. Cultured cerebellar granule neurons (CGN) survive when maintained in high K(+) (25 mm) but undergo apoptosis when switched to low K(+) (5 mm). GDF-15 prevented death of CGN in low K(+). This effect could be blocked by phosphatidylinositol 3-kinase/Akt pathway inhibitors LY294002 or wortmannin. In contrast, mitogen-activated protein kinase (MEK)/extracellular-signal-regulated kinase (ERK) pathway inhibitors U0126 and PD98059 potentiated GDF-15 mediated survival and prevented cell death in low K(+) even without factor treatment. Immunoblots revealed GDF-15-induced phosphorylation of Akt and glycogen synthase kinase-3beta. This activation was suppressed by phosphatidylinositol 3-kinase inhibitors. Low K(+) induced delayed and persistent ERK activation, which was blocked by MEK inhibitors or GDF-15. ERK activation induced c-Jun, a member of the AP-1 transcription factor family. GDF-15 or U0126 prevented c-Jun activation. Furthermore, we show that GDF-15 prevented generation of reactive oxygen species, a known activator of ERK. Together, our data suggest that GDF-15 prevents apoptosis in CGN by activating Akt and inhibiting endogenously active ERK.
Subramaniam
Srinivasa
S
Neuroanatomy and Interdisciplinary Center for Neurosciences (IZN), University of Heidelberg, Im Neuenheimer Feld 307, D-69120 Heidelberg, Germany.
Strelau
Jens
J
Unsicker
Klaus
K
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001921:Brain / Q000166:cytology*; D002070:Butadienes / Q000494:pharmacology; D016923:Cell Death; D002454:Cell Differentiation; D002455:Cell Division; D002470:Cell Survival; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D016207:Cytokines / Q000502:physiology*; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D055436:Growth Differentiation Factor 15; D006801:Humans; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D048031:JNK Mitogen-Activated Protein Kinases; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011188:Potassium / Q000378:metabolism / Q000494:pharmacology*; D011419:Propidium / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins / Q000378:metabolism; D013997:Time Factors; D000077191:Wortmannin
D000730:Androstadienes; D002070:Butadienes; D002867:Chromones; D016207:Cytokines; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D055436:Growth Differentiation Factor 15; D048031:JNK Mitogen-Activated Protein Kinases; D007770:L-Lactate Dehydrogenase; D020928:Mitogen-Activated Protein Kinases; D009025:Morpholines; D009570:Nitriles; D010100:Oxygen; D019869:Phosphatidylinositol 3-Kinases; D011188:Potassium; D011419:Propidium; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D000077191:Wortmannin; C526140:GDF15 protein, human; C526142:Gdf15 protein, rat; C113580:U 0126; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494918:AKT1 protein, human; C494920:Akt1 protein, rat