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The role of TRADD in TRAIL-induced apoptosis and signaling

Xiumei Cao1, Yelena L Pobezinskaya, Michael J Morgan

  • 1Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|December 29, 2010
PubMed

Insights

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) signaling involves TRADD for cell survival. TRADD limits FADD binding, reducing cancer cell apoptosis and impacting TRAIL-based cancer therapies.

Area of Science:

  • Cellular and Molecular Biology
  • Immunology
  • Oncology

Background:

  • TRAIL induces cancer cell apoptosis, making it a promising anticancer therapy.
  • TRAIL signaling pathways, particularly the roles of adaptor proteins like TRADD and RIP1, are not fully understood.
  • TRADD's function in TRAIL-induced apoptosis has been controversial.

Purpose of the Study:

  • To investigate the role of TRADD in TRAIL-mediated apoptosis.
  • To elucidate the molecular mechanisms by which TRADD influences TRAIL signaling.
  • To determine the implications of TRADD's function for TRAIL-based cancer therapies.

Main Methods:

  • Utilized wild-type and Tradd(-/-) mouse embryonic fibroblasts (MEFs) and primary keratinocytes.
  • Assessed TRAIL-induced apoptosis sensitivity using recombinant mouse TRAIL (rmTRAIL) and cycloheximide (CHX).
  • Investigated protein recruitment to the TRAIL-receptor complex using biochemical assays and analyzed MAP kinase ERK activation.

Main Results:

  • Tradd(-/-) MEFs exhibited hypersensitivity to TRAIL-induced apoptosis compared to wild-type MEFs.
  • TRADD recruitment to the TRAIL-receptor complex was demonstrated, mediating RIP1 recruitment.
  • TRADD deficiency led to increased FADD recruitment and reduced early ERK activation, enhancing TRAIL sensitivity.

Conclusions:

  • TRADD plays a crucial survival role in TRAIL signaling by limiting FADD binding and mediating RIP1-dependent nonapoptotic pathways.
  • TRADD's function in regulating apoptosis has significant implications for the development of TRAIL-receptor agonists in cancer treatment.
  • Understanding TRADD's role can help optimize TRAIL-based therapies to overcome resistance and enhance efficacy.

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