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Poster Display session 1

4808 - NORE1A induces a feedback termination of TNF signaling by antagonizing TNFR1 through ITCH-mediated destruction complex


28 Sep 2019


Poster Display session 1


Basic Science

Tumour Site


Jieun Ahn


Annals of Oncology (2019) 30 (suppl_5): v1-v24. 10.1093/annonc/mdz238


J. Ahn, K. Ko, M. Lee, S. Chi

Author affiliations

  • College Of Life Science, KOREA UNIVSERSITY, 02841 - Seoul/KR


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Abstract 4808


NORE1A/RASSF5 is a tumor suppressor that is commonly inactivated in a variety of cancers. NORE1A is frequently down-regulated during tumor development and its inactivation often correlates with up-regulation of Ras activity. Although NORE1A was reported to be activated by NF-kB, its role in NF-kB signaling and the underlying mechanism have not been addressed. In this study, we explored the role for NORE1A in the regulation and function of the TNF-NF-kB pathway.


NORE1A effect on TNF regulation of inflammation, growth, and apoptosis was examined by flow cytometry, migration and invasion, and apoptosis assays. NORE1A regulation of TNF-NF-kB signaling was analyzed by quantitative RT-PCR, immunoblot, immunoprecipitation, and promoter luciferase assay.


Upon exposure to TNF-a, NORE1A is induced by NF-kB signaling at the level of transcription while its activation suppresses TNF activation of NF-kB, indicating that NORE1A functions as a feedback terminator of TNF-NF-kB signaling. As predicted, NORE1A blocks TNF activation of pro-inflammatory gene transcription, epithelial-to-mesenchymal transition (EMT), invasion and migration. Mechanistically, NORE1A binds directly to TNF receptor I (TNFR1) and ubiquitin E3 ligase ITCH to promote ITCH-mediated K48-linked ubiquitination of TNFR1 and subsequent lysosomal degradation. Additionally, we identified that the PPXY motif of NORE1A interacts directly with ITCH using a series of deletion mutants. This interaction protects BAX from ITCH-mediated ubiquitination and thus activates its apoptotic function. NORE1A interaction with ITCH plays a crucial role for both TNFR1 degradation and BAX stabilization and activation.


In this study, we demonstrate first that NORE1A is a feedback terminator of TNF-NF-kB signaling, which directly antagonizes TNFR1 by facilitating the ITCH-TNFR1 interaction. Our study also shows that NORE1A binding to ITCH releases ITCH from BAX and activates BAX-mediated apoptosis. These data illuminate the mechanistic consequence of NORE1A inactivation in tumorigenesis.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Sung-gil, Chi.


Has not received any funding.


All authors have declared no conflicts of interest.

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