PEA-15 (phosphoprotein enriched in astrocytes 15 kDa) 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 small interfering RNA (siRNA)-mediated downregulation of endogenous PEA-15 results in the sensitization to glucose withdrawal-mediated cell death. This antiapoptotic 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 extracellular-regulated kinase (ERK)1/2 in glioblastoma cells and the PEA-15-dependent protection from glucose deprivation-induced cell death requires ERK1/2 signaling. PEA-15 transcriptionally upregulates 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, for example in perinecrotic areas of glioblastomas. © 2008 Nature Publishing Group All rights reserved.

Eckert, A., Bã¶ck, B. C., Tagscherer, K. E., Haas, T. L., Grund, K., Sykora, J., Herold-Mende, C., Ehemann, V., Hollstein, M., Chneiweiss, H., Wiestler, O. D., Walczak, H., Roth, W., The PEA-15/PED protein protects glioblastoma cells from glucose deprivation-induced apoptosis via the ERK/MAP kinase pathway, <<ONCOGENE>>, 2008; 27 (8): 1155-1166. [doi:10.1038/sj.onc.1210732] [http://hdl.handle.net/10807/114355]

The PEA-15/PED protein protects glioblastoma cells from glucose deprivation-induced apoptosis via the ERK/MAP kinase pathway

Haas, Tobias Longin;
2008

Abstract

PEA-15 (phosphoprotein enriched in astrocytes 15 kDa) 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 small interfering RNA (siRNA)-mediated downregulation of endogenous PEA-15 results in the sensitization to glucose withdrawal-mediated cell death. This antiapoptotic 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 extracellular-regulated kinase (ERK)1/2 in glioblastoma cells and the PEA-15-dependent protection from glucose deprivation-induced cell death requires ERK1/2 signaling. PEA-15 transcriptionally upregulates 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, for example in perinecrotic areas of glioblastomas. © 2008 Nature Publishing Group All rights reserved.
2008
Inglese
Eckert, A., Bã¶ck, B. C., Tagscherer, K. E., Haas, T. L., Grund, K., Sykora, J., Herold-Mende, C., Ehemann, V., Hollstein, M., Chneiweiss, H., Wiestler, O. D., Walczak, H., Roth, W., The PEA-15/PED protein protects glioblastoma cells from glucose deprivation-induced apoptosis via the ERK/MAP kinase pathway, <<ONCOGENE>>, 2008; 27 (8): 1155-1166. [doi:10.1038/sj.onc.1210732] [http://hdl.handle.net/10807/114355]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10807/114355
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