Tumor necrosis factor-related apoptosis-inducing ligand-induced death-inducing signaling complex and its modulation by c-FLIP and PED/PEA-15 in glioma cells

Chang Xiao, Bao Feng Yang, Neda Asadi, Francesco Beguinot, Chunhai Hao

Research output: Contribution to journalArticle

158 Citations (Scopus)

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can trigger apoptosis in some tumor cells but not other tumor cells. To explore the signal transduction events in TRAIL-triggered apoptosis and its modulation in nontransfected tumor cells, we analyzed TRAIL-induced death-inducing signaling complex (DISC) in TRAIL-sensitive and -resistant glioma cells. Caspase-8 and caspase-10 were recruited to the DISC, where they were proteolytically activated to initiate apoptosis in TRAIL-sensitive glioma cells. Caspase-8 and caspase-10 were also recruited to the DISC in TRAIL-resistant cells, but their further activation was inhibited by two antiapoptotic proteins termed cellular Fas-associated death domain-like interleukin-1β-converting enzyme-inhibitory protein (c-FLIP) and phosphoprotein enriched in diabetes/phosphoprotein enriched in astrocytes-15kDa (PED/PEA-15). Both long and short forms of c-FLIP were recruited to the DISC, where the long form c-FLIP was cleaved to produce intermediate fragments. Of the three isoforms of PED/PEA-15 proteins, only the doubly phosphorylated form was expressed and recruited to the DISC in TRAIL-resistant cells, indicating that the phosphorylation status of PED/PEA-15 determines its recruitment in the cells. Treatment with calcium/calmodulin-dependent protein kinase inhibitor rescued TRAIL sensitivity in TRAIL-resistant cells, providing a potential new approach to sensitize the cells to TRAIL-induced apoptosis.

Original languageEnglish (US)
Pages (from-to)25020-25025
Number of pages6
JournalJournal of Biological Chemistry
Volume277
Issue number28
DOIs
StatePublished - Jul 12 2002
Externally publishedYes

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Death Domain Receptor Signaling Adaptor Proteins
Phosphoproteins
Medical problems
Glioma
Astrocytes
Tumor Necrosis Factor-alpha
Modulation
Apoptosis
Ligands
Caspase 10
Tumors
Caspase 8
Cells
Caspase 1
Signal transduction
Calcium-Calmodulin-Dependent Protein Kinases
Phosphorylation
Proteins
Protein Kinase Inhibitors
Protein Isoforms

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Tumor necrosis factor-related apoptosis-inducing ligand-induced death-inducing signaling complex and its modulation by c-FLIP and PED/PEA-15 in glioma cells. / Xiao, Chang; Yang, Bao Feng; Asadi, Neda; Beguinot, Francesco; Hao, Chunhai.

In: Journal of Biological Chemistry, Vol. 277, No. 28, 12.07.2002, p. 25020-25025.

Research output: Contribution to journalArticle

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