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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death

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Distinct signaling pathways in TRAIL- versus tumor necrosis factor-induced apoptosis

Zhaoyu Jin1, Wafik S El-Deiry

  • 1Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.

Molecular and Cellular Biology
|August 31, 2006
PubMed

Insights

Tumor necrosis factor (TNF) signaling differs from Fas-L/TRAIL-induced apoptosis. RIP, not TRADD, is crucial for TNF-induced apoptosis in tumor cells, distinct from other death receptor pathways.

Area of Science:

  • Molecular and Cellular Biology
  • Immunology
  • Cancer Biology

Background:

  • Tumor necrosis factor receptor 1 (TNFR1) signaling initiates cascades involving adaptor proteins like TRADD, RIP, TRAF2, and FADD.
  • Current models propose these adaptors mediate NF-kappaB, JNK activation, and apoptosis following TNF binding.
  • The precise roles and interplay of these adaptors in TNF-induced apoptosis, especially in cancer cells, require further elucidation.

Purpose of the Study:

  • To investigate the distinct mechanisms of TNF-induced apoptosis compared to Fas-L and TRAIL.
  • To clarify the roles of TRADD and RIP in TNF signaling and apoptosis.
  • To determine the necessity of TRADD, RIP, and FADD in TNF-induced apoptosis in human tumor cells.

Main Methods:

  • Utilized stable short-hairpin RNA (shRNA) knockdown (KD) cell lines targeting TRADD, RIP, TRAF2, and FADD.
  • Performed TNF death-inducing signaling complex immunoprecipitation to analyze protein-protein interactions.
  • Assessed apoptosis induction by TNF, Fas-L, and TRAIL in KD cells.

Main Results:

  • Demonstrated competitive binding of TRADD and RIP to TNFR1; TRAF2 recruitment requires TRADD.
  • FADD is essential for Fas-L/TRAIL-induced apoptosis but not TNF-induced apoptosis.
  • TRADD is dispensable, while RIP is required for TNF-induced apoptosis in human tumor cells; RIP KD abrogates complex II formation.

Conclusions:

  • TNF triggers apoptosis through a mechanism distinct from Fas-L and TRAIL.
  • TRADD plays a role in TNF-induced c-Jun phosphorylation, but RIP is critical for TNF-induced apoptosis complex II formation.
  • The distinct signaling pathways highlight potential therapeutic targets in cancer.

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