[The PEA-15 protein induces resistance against glucose deprivation-induced cell death via the ERK/MAP kinase pathway].
PEA-15 (Phosphoprotein enriched in astrocytes 15 kD) is a death effector domain-containing protein, which is involved in the regulation of apoptotic cell death. Since PEA-15 is highly expressed in cells of glial origin, we studied the role of PEA-15 in human malignant brain tumors. Immunohistochemical analysis of PEA-15 expression shows strong immunoreactivity in astrocytomas and glioblastomas. Phosphorylation of PEA-15 at Ser116 is found in vivo in perinecrotic areas in glioblastomas and in vitro after glucose deprivation of glioblastoma cells. Overexpression of PEA-15 induces a marked resistance against glucose deprivation-induced apoptosis, whereas siRNA-mediated down-regulation of endogenous PEA-15 results in the sensitization to glucose withdrawal-mediated cell death. This anti-apoptotic activity of PEA-15 under low glucose conditions depends on its phosphorylation at Ser116 Moreover, siRNA-mediated knockdown of PEA-15 abolishes the tumorigenicity of U87MG glioblastoma cells in vivo. PEA-15 regulates the level of phosphorylated ERK1/2 in glioblastoma cells and the PEA-15-dependent protection from glucose deprivation-induced cell death requires ERK1/2 signaling. PEA-15 transcriptionally up-regulates the glucose transporter 3, which is abrogated by the inhibition of ERK1/2 phosphorylation. Taken together, our findings suggest that Ser116-phosphorylated PEA-15 renders glioma cells resistant to glucose deprivation-mediated cell death as encountered in poor microenvironments, e.g. in perinecrotic areas of glioblastomas.
Roth
W
W
Pathologisches Institut, Universitäisklinikum Heidelberg.
Eckert
A
A
Böck
B
B
Schirmacher
P
P
Wiestler
O D
OD
D051017:Apoptosis Regulatory Proteins; D001253:Astrocytes / Q000166:cytology / Q000473:pathology; D001254:Astrocytoma / Q000473:pathology; D001932:Brain Neoplasms / Q000473:pathology; D016923:Cell Death; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005909:Glioblastoma / Q000473:pathology; D005947:Glucose / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D010750:Phosphoproteins / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; D047908:Intracellular Signaling Peptides and Proteins; C092039:PEA15 protein, human; D010750:Phosphoproteins; D048049:Extracellular Signal-Regulated MAP Kinases; D005947:Glucose