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Human astrocytes are resistant to Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis.
J Neurosci. 2006 Mar 22; 26(12):3299-308.JN

Abstract

Human astrocytes express Fas yet are resistant to Fas-induced apoptosis. Here, we report that calcium/calmodulin-dependent protein kinase II (CaMKII) is constitutively activated in human astrocytes and protects the cells from apoptotic stimulation by Fas agonist. Once stimulated, Fas recruits Fas-associated death domain and caspase-8 for the assembly of the death-inducing signaling complex (DISC); however, caspase-8 cleavage is inhibited in the DISC. Inhibition of CaMKII kinase activity inhibits the expression of phosphoprotein enriched astrocytes-15 kDa/phosphoprotein enriched in diabetes (PEA-15/PED) and cellular Fas-associated death domain-like interleukin-1beta-converting enzyme-inhibitory protein (c-FLIP), thus releasing their inhibition of caspase-8 cleavage. Inhibition of PEA-15/PED or c-FLIP by small interfering RNA sensitizes human astrocytes to Fas-induced apoptosis. In contrast, inhibition of CaMKII, PEA-15, or c-FLIP does not affect the sensitivity of human astrocytes to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). TRAIL death receptors (DR4, DR5) are weakly expressed at mRNA, protein, and cell surface levels and thus fail to mediate the assembly of the DISC in human astrocytes. Overexpression of DR5 restores TRAIL signaling pathways and sensitizes the human astrocytes to TRAIL-induced apoptosis if CaMKII kinase activity or expression of PEA-15 and c-FLIP is inhibited; the results suggest that CaMKII-mediated pathways prevent TRAIL-induced apoptosis in human astrocytes under conditions in which TRAIL death receptors are upregulated. This study has therefore identified the molecular mechanisms that protect normal human astrocytes from apoptosis induced by Fas ligand and TRAIL.

Authors+Show Affiliations

Department of Pathology and Laboratory Medicine, Center of Neurodegenerative Disease, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16554480

Citation

Song, Jin H., et al. "Human Astrocytes Are Resistant to Fas Ligand and Tumor Necrosis Factor-related Apoptosis-inducing Ligand-induced Apoptosis." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 26, no. 12, 2006, pp. 3299-308.
Song JH, Bellail A, Tse MC, et al. Human astrocytes are resistant to Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. J Neurosci. 2006;26(12):3299-308.
Song, J. H., Bellail, A., Tse, M. C., Yong, V. W., & Hao, C. (2006). Human astrocytes are resistant to Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 26(12), 3299-308.
Song JH, et al. Human Astrocytes Are Resistant to Fas Ligand and Tumor Necrosis Factor-related Apoptosis-inducing Ligand-induced Apoptosis. J Neurosci. 2006 Mar 22;26(12):3299-308. PubMed PMID: 16554480.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Human astrocytes are resistant to Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. AU - Song,Jin H, AU - Bellail,Anita, AU - Tse,Margaret C L, AU - Yong,V Wee, AU - Hao,Chunhai, PY - 2006/3/24/pubmed PY - 2006/4/15/medline PY - 2006/3/24/entrez SP - 3299 EP - 308 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J Neurosci VL - 26 IS - 12 N2 - Human astrocytes express Fas yet are resistant to Fas-induced apoptosis. Here, we report that calcium/calmodulin-dependent protein kinase II (CaMKII) is constitutively activated in human astrocytes and protects the cells from apoptotic stimulation by Fas agonist. Once stimulated, Fas recruits Fas-associated death domain and caspase-8 for the assembly of the death-inducing signaling complex (DISC); however, caspase-8 cleavage is inhibited in the DISC. Inhibition of CaMKII kinase activity inhibits the expression of phosphoprotein enriched astrocytes-15 kDa/phosphoprotein enriched in diabetes (PEA-15/PED) and cellular Fas-associated death domain-like interleukin-1beta-converting enzyme-inhibitory protein (c-FLIP), thus releasing their inhibition of caspase-8 cleavage. Inhibition of PEA-15/PED or c-FLIP by small interfering RNA sensitizes human astrocytes to Fas-induced apoptosis. In contrast, inhibition of CaMKII, PEA-15, or c-FLIP does not affect the sensitivity of human astrocytes to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). TRAIL death receptors (DR4, DR5) are weakly expressed at mRNA, protein, and cell surface levels and thus fail to mediate the assembly of the DISC in human astrocytes. Overexpression of DR5 restores TRAIL signaling pathways and sensitizes the human astrocytes to TRAIL-induced apoptosis if CaMKII kinase activity or expression of PEA-15 and c-FLIP is inhibited; the results suggest that CaMKII-mediated pathways prevent TRAIL-induced apoptosis in human astrocytes under conditions in which TRAIL death receptors are upregulated. This study has therefore identified the molecular mechanisms that protect normal human astrocytes from apoptosis induced by Fas ligand and TRAIL. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/16554480/Human_astrocytes_are_resistant_to_Fas_ligand_and_tumor_necrosis_factor_related_apoptosis_inducing_ligand_induced_apoptosis_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=16554480 DB - PRIME DP - Unbound Medicine ER -