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
5729 - Expression of mutant p53 affects cancer cell sensitivity to topotecan
Presenter: Rimma Mingaleeva
Session: Poster Display session 1
Resources:
Abstract
5725 - Breast cancer organoids a new tool for the prediction of drugs penetration and patient’outcome
Presenter: Giuseppina Roscigno
Session: Poster Display session 1
Resources:
Abstract
5680 - Aptamer-mediated exosomes detection for early breast cancer identification.
Presenter: Cristina Quintavalle
Session: Poster Display session 1
Resources:
Abstract
2460 - MicroRNA-181c promotes tamoxifen resistance in breast cancer cells via upregulation Akt/mTOR axis
Presenter: Alexander Scherbakov
Session: Poster Display session 1
Resources:
Abstract
3751 - Spatio-temporal separation of tumor infiltrating CD8+ T-cells and HER2/neu+ tumor cells in tumor-immune milieu of infiltrating ductal carcinoma of the breast
Presenter: Sandhya Sreedharan
Session: Poster Display session 1
Resources:
Abstract
4664 - Large genomic rearrangements in BRCA1 and BRCA2 genes in the Portuguese population.
Presenter: Joao Pinto
Session: Poster Display session 1
Resources:
Abstract
4611 - Non-BRCA1/2 hereditary breast and ovarian cancer: findings from a multidisciplinary program
Presenter: Ana Monteiro
Session: Poster Display session 1
Resources:
Abstract
5340 - Quantitative imaging and characterization of collagen patterns in high grade serous ovarian carcinoma (HGSOC)
Presenter: Ruby Huang
Session: Poster Display session 1
Resources:
Abstract
4209 - Semiquantitative assessment of vimentin expression in prostate cancer (PC)
Presenter: Marina Puchinskaya
Session: Poster Display session 1
Resources:
Abstract
3309 - Heat Shock Protein 90 chaperones and Protein Kinase D3 regulates androgen-independent prostate cancer development
Presenter: Attila Varga
Session: Poster Display session 1
Resources:
Abstract