PMID- 12514175
OWN - NLM
STAT- MEDLINE
DCOM- 20030514
LR  - 20211203
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 278
IP  - 11
DP  - 2003 Mar 14
TI  - Growth differentiation factor-15 prevents low potassium-induced cell death of 
      cerebellar granule neurons by differential regulation of Akt and ERK pathways.
PG  - 8904-12
AB  - 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.
FAU - Subramaniam, Srinivasa
AU  - Subramaniam S
AD  - Neuroanatomy and Interdisciplinary Center for Neurosciences (IZN), University of 
      Heidelberg, Im Neuenheimer Feld 307, D-69120 Heidelberg, Germany.
FAU - Strelau, Jens
AU  - Strelau J
FAU - Unsicker, Klaus
AU  - Unsicker K
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20030103
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Androstadienes)
RN  - 0 (Butadienes)
RN  - 0 (Chromones)
RN  - 0 (Cytokines)
RN  - 0 (DNA, Complementary)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (GDF15 protein, human)
RN  - 0 (Gdf15 protein, rat)
RN  - 0 (Growth Differentiation Factor 15)
RN  - 0 (Morpholines)
RN  - 0 (Nitriles)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Recombinant Proteins)
RN  - 0 (U 0126)
RN  - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one)
RN  - 36015-30-2 (Propidium)
RN  - EC 1.1.1.27 (L-Lactate Dehydrogenase)
RN  - EC 2.7.11.1 (AKT1 protein, human)
RN  - EC 2.7.11.1 (Akt1 protein, rat)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - RWP5GA015D (Potassium)
RN  - S88TT14065 (Oxygen)
RN  - XVA4O219QW (Wortmannin)
SB  - IM
MH  - Androstadienes/pharmacology
MH  - Animals
MH  - Apoptosis
MH  - Blotting, Western
MH  - Brain/*cytology
MH  - Butadienes/pharmacology
MH  - *Cell Death
MH  - Cell Differentiation
MH  - Cell Division
MH  - Cell Survival
MH  - Cells, Cultured
MH  - Chromones/pharmacology
MH  - Cytokines/*physiology
MH  - DNA, Complementary/metabolism
MH  - Dose-Response Relationship, Drug
MH  - Enzyme Inhibitors/pharmacology
MH  - Growth Differentiation Factor 15
MH  - Humans
MH  - Immunoblotting
MH  - In Situ Nick-End Labeling
MH  - JNK Mitogen-Activated Protein Kinases
MH  - L-Lactate Dehydrogenase/metabolism
MH  - MAP Kinase Signaling System
MH  - Mitogen-Activated Protein Kinases/*metabolism
MH  - Morpholines/pharmacology
MH  - Neurons/*metabolism
MH  - Nitriles/pharmacology
MH  - Oxygen/metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphorylation
MH  - Potassium/metabolism/*pharmacology
MH  - Propidium/pharmacology
MH  - *Protein Serine-Threonine Kinases
MH  - Proto-Oncogene Proteins/*metabolism
MH  - Proto-Oncogene Proteins c-akt
MH  - Rats
MH  - Rats, Wistar
MH  - Reactive Oxygen Species
MH  - Recombinant Proteins/metabolism
MH  - Time Factors
MH  - Wortmannin
EDAT- 2003/01/07 04:00
MHDA- 2003/05/15 05:00
CRDT- 2003/01/07 04:00
PHST- 2003/01/07 04:00 [pubmed]
PHST- 2003/05/15 05:00 [medline]
PHST- 2003/01/07 04:00 [entrez]
AID - S0021-9258(19)71255-1 [pii]
AID - 10.1074/jbc.M210037200 [doi]
PST - ppublish
SO  - J Biol Chem. 2003 Mar 14;278(11):8904-12. doi: 10.1074/jbc.M210037200. Epub 2003 
      Jan 3.