Human astrocytes are resistant to fas ligand and tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis

Jin H. Song, Anita Bellail, Margaret C.L. Tse, V. Wee Yong, Chunhai Hao

Research output: Contribution to journalArticle

79 Citations (Scopus)

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-1β-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 ofhumanastrocytes 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.

Original languageEnglish (US)
Pages (from-to)3299-3308
Number of pages10
JournalJournal of Neuroscience
Volume26
Issue number12
DOIs
StatePublished - Mar 22 2006
Externally publishedYes

Fingerprint

Fas Ligand Protein
Astrocytes
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Tumor Necrosis Factor-alpha
Apoptosis
Ligands
Death Domain Receptor Signaling Adaptor Proteins
Phosphoproteins
Caspase 8
TNF-Related Apoptosis-Inducing Ligand Receptors
Death Domain Receptors
Phosphotransferases
Caspase 1
Calcium-Calmodulin-Dependent Protein Kinases
Small Interfering RNA
Membrane Proteins
Messenger RNA

Keywords

  • Apoptosis
  • Astrocytes
  • c-FLIP
  • CaMKII
  • Fas
  • TRAIL

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Human astrocytes are resistant to fas ligand and tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. / Song, Jin H.; Bellail, Anita; Tse, Margaret C.L.; Yong, V. Wee; Hao, Chunhai.

In: Journal of Neuroscience, Vol. 26, No. 12, 22.03.2006, p. 3299-3308.

Research output: Contribution to journalArticle

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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-1β-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 ofhumanastrocytes 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.

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