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Related Experiment Videos

Stress-induced decrease in TRAF2 stability is mediated by Siah2.

Hasem Habelhah1, Ian J Frew, Aaron Laine

  • 1Ruttenberg Cancer Center and Department of Biochemistry and Molecular Biology, Mount Sinai School of Medicine, New York, NY 10029, USA.

The EMBO Journal
|November 2, 2002
PubMed
Summary
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The E3 ubiquitin ligase Siah2 targets TRAF2 for degradation under cellular stress. This regulation impacts stress signaling pathways, including JNK and NF-kappaB, and influences apoptosis.

Area of Science:

  • Cellular biology
  • Molecular signaling
  • Stress response pathways

Background:

  • Tumor necrosis factor receptor-associated factor 2 (TRAF2) is crucial for cellular responses to stress and cytokines.
  • TRAF2 regulates key stress-signaling cascades, including JNK and NF-kappaB pathways.
  • Understanding TRAF2 regulation is vital for comprehending cellular stress responses.

Purpose of the Study:

  • To investigate the role of Siah2 in the regulation of TRAF2 stability.
  • To elucidate the mechanism by which Siah2 affects TRAF2 ubiquitylation and degradation.
  • To determine the functional consequences of Siah2-mediated TRAF2 regulation on stress-induced signaling and apoptosis.

Main Methods:

  • In vitro ubiquitylation and degradation assays using wild-type and RING mutant Siah2.

Related Experiment Videos

  • In vivo studies in wild-type and Siah2(-/-) mouse embryo fibroblasts (MEFs) under stress conditions (TNF-alpha, actinomycin D).
  • Analysis of JNK activity, NF-kappaB transcriptional activation, and apoptosis induction.

    • Main Results:

    • Wild-type Siah2, but not its RING mutant, targets TRAF2 for ubiquitylation and degradation in vitro.
    • Siah2 promotes TRAF2 degradation under stress conditions in vivo, leading to a prolonged TRAF2 half-life in Siah2(-/-) MEFs.
    • Siah2 expression decreases TNF-alpha-induced JNK activity and NF-kappaB activation, and enhances apoptosis.

    Conclusions:

    • Siah2 acts as a negative regulator of TRAF2 stability.
    • Siah2-mediated degradation of TRAF2 plays a significant role in modulating stress-induced signaling pathways.
    • This finding identifies Siah2 as a key player in the cellular response to stress via TRAF2 regulation.