Abstract 4808
Background
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.
Methods
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.
Results
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.
Conclusions
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.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
4883 - A New Population Model Validated Pharmacokinetic Similarity of HLX01 and Rituximab in B-Cell Lymphoma
Presenter: Yuankai Shi
Session: Poster Display session 1
Resources:
Abstract
4908 - Efficacy of salvage therapy in the treatment of Helicobacter pylori-positive gastric low-grade mucosa-associated lymphoid tissue lymphoma
Presenter: Sung-Nam Lim
Session: Poster Display session 1
Resources:
Abstract
2360 - Mutational analysis of extranodal marginal zone lymphoma using next generation sequencing
Presenter: Seok Jae Huh
Session: Poster Display session 1
Resources:
Abstract
2430 - Clinical features, treatment and outcomes of colon and rectum mucosa-associated lymphoid tissue (MALT) lymphoma: Literature reviews published in English between 1993 and 2017
Presenter: Jeong Yeon Kim
Session: Poster Display session 1
Resources:
Abstract
4654 - Splenic marginal zone lymphoma: clinical characteristics and prognostic factors in a series of 52 patients
Presenter: Guldane Cengiz Seval
Session: Poster Display session 1
Resources:
Abstract
1732 - Safety and efficacy of Bendamustine and Rituximab (BR) regimen in Indian Chronic Lymphocytic Leukemia patients
Presenter: Ajay Gogia
Session: Poster Display session 1
Resources:
Abstract
5784 - N-terminal B-type natriuretic peptide (NT-proBNP) as an independed prognostic marker for patients with newly diagnosed multiple myeloma complicated by dialysis-dependent renal failure
Presenter: Sergey Semochkin
Session: Poster Display session 1
Resources:
Abstract
836 - The first-line effect of Bortezomib-based Therapy on Clinical Outcomes for Taiwanese Patients with multiple myeloma
Presenter: Ching-Liang Ho
Session: Poster Display session 1
Resources:
Abstract
2085 - Impact of Donor Lymphocyte Infusion in Relapsing Myeloid Neoplasms Post Allogeneic Hematopoietic Stem Cell Transplantation
Presenter: Hanafy Hafez
Session: Poster Display session 1
Resources:
Abstract
6079 - Invasive fungal diseases in patients with Hodgkin’s lymphoma before and after allogeneic hematopoietic stem cell transplantation
Presenter: Marina Popova
Session: Poster Display session 1
Resources:
Abstract