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Intracellular mechanisms of TRAIL: apoptosis through mitochondrial-dependent and -independent pathways.
Oncogene. 2001 Apr 19; 20(17):2122-33.O

Abstract

Tumor necrosis (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family of cytokines that promotes apoptosis. TRAIL induces apoptosis via death receptors (DR4 and DR5) in a wide variety of tumor cells but not in normal cells. The objectives of this study are to investigate the intracellular mechanisms by which TRAIL induces apoptosis. The death receptor Fas, upon ligand binding, trimerizes and recruits the adaptor protein FADD through the cytoplasmic death domain of Fas. FADD then binds and activates procaspase-8. It is unclear whether FADD is required for TRAIL-induced apoptosis. Here we show that the signaling complex of DR4/DR5 is assembled in response to TRAIL binding. FADD and caspase-8, but not caspase-10, are recruited to the receptor, and cells deficient in either FADD or caspase-8 blocked TRAIL-induced apoptosis. In addition, TRAIL initiates the activation of caspases, the loss of mitochondrial transmembrane potential (Deltapsi(m)), the cleavage of BID, and the redistribution of mitochondrial cytochrome c. Treatment of Jurkat cells with cyclosporin A delayed TRAIL-induced Deltapsi(m), caspase-3 activation and apoptosis. Similarly, Overexpression of Bcl-2 or Bcl-X(L) delayed, but did not inhibit, TRAIL-induced Deltapsi(m) and apoptosis. In contrast, XIAP, cowpox virus CrmA and baculovirus p35 inhibited TRAIL-induced apoptosis. These data suggest that death receptors (DR4 and DR5) and Fas receptors induced apoptosis through identical signaling pathway, and TRAIL-induced apoptosis via both mitochondrial-dependent and -independent pathways.

Authors+Show Affiliations

Department of Pharmaceutical Sciences, University of Maryland - School of Pharmacy, 20 N Pine Street, Baltimore, Maryland MD 21201, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

11360196

Citation

Suliman, A, et al. "Intracellular Mechanisms of TRAIL: Apoptosis Through Mitochondrial-dependent and -independent Pathways." Oncogene, vol. 20, no. 17, 2001, pp. 2122-33.
Suliman A, Lam A, Datta R, et al. Intracellular mechanisms of TRAIL: apoptosis through mitochondrial-dependent and -independent pathways. Oncogene. 2001;20(17):2122-33.
Suliman, A., Lam, A., Datta, R., & Srivastava, R. K. (2001). Intracellular mechanisms of TRAIL: apoptosis through mitochondrial-dependent and -independent pathways. Oncogene, 20(17), 2122-33.
Suliman A, et al. Intracellular Mechanisms of TRAIL: Apoptosis Through Mitochondrial-dependent and -independent Pathways. Oncogene. 2001 Apr 19;20(17):2122-33. PubMed PMID: 11360196.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Intracellular mechanisms of TRAIL: apoptosis through mitochondrial-dependent and -independent pathways. AU - Suliman,A, AU - Lam,A, AU - Datta,R, AU - Srivastava,R K, PY - 2000/07/27/received PY - 2001/01/12/revised PY - 2001/01/18/accepted PY - 2001/5/22/pubmed PY - 2001/6/8/medline PY - 2001/5/22/entrez SP - 2122 EP - 33 JF - Oncogene JO - Oncogene VL - 20 IS - 17 N2 - Tumor necrosis (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family of cytokines that promotes apoptosis. TRAIL induces apoptosis via death receptors (DR4 and DR5) in a wide variety of tumor cells but not in normal cells. The objectives of this study are to investigate the intracellular mechanisms by which TRAIL induces apoptosis. The death receptor Fas, upon ligand binding, trimerizes and recruits the adaptor protein FADD through the cytoplasmic death domain of Fas. FADD then binds and activates procaspase-8. It is unclear whether FADD is required for TRAIL-induced apoptosis. Here we show that the signaling complex of DR4/DR5 is assembled in response to TRAIL binding. FADD and caspase-8, but not caspase-10, are recruited to the receptor, and cells deficient in either FADD or caspase-8 blocked TRAIL-induced apoptosis. In addition, TRAIL initiates the activation of caspases, the loss of mitochondrial transmembrane potential (Deltapsi(m)), the cleavage of BID, and the redistribution of mitochondrial cytochrome c. Treatment of Jurkat cells with cyclosporin A delayed TRAIL-induced Deltapsi(m), caspase-3 activation and apoptosis. Similarly, Overexpression of Bcl-2 or Bcl-X(L) delayed, but did not inhibit, TRAIL-induced Deltapsi(m) and apoptosis. In contrast, XIAP, cowpox virus CrmA and baculovirus p35 inhibited TRAIL-induced apoptosis. These data suggest that death receptors (DR4 and DR5) and Fas receptors induced apoptosis through identical signaling pathway, and TRAIL-induced apoptosis via both mitochondrial-dependent and -independent pathways. SN - 0950-9232 UR - https://www.unboundmedicine.com/medline/citation/11360196/Intracellular_mechanisms_of_TRAIL:_apoptosis_through_mitochondrial_dependent_and__independent_pathways_ L2 - https://doi.org/10.1038/sj.onc.1204282 DB - PRIME DP - Unbound Medicine ER -