ArticleCell death & disease2013
The E3 ubiquitin ligase Itch regulates tumor suppressor protein RASSF5/NORE1 stability in an acetylation-dependent manner.
Article in Cell death & disease, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 47 citations in OpenAlex.
- The expanding landscape of Deltex: signaling crosstalk and clinical implications.Cellular and molecular life sciences : CMLS · 2026Review
- p27 specifically decreases in squamous carcinoma, and mediates NNK-induced transformation of human bronchial epithelial cells.Journal of cellular and molecular medicine · 2024Article
- UBE4B interacts with the ITCH E3 ubiquitin ligase to induce Ku70 and c-FLIPL polyubiquitination and enhanced neuroblastoma apoptosis.Cell death & disease · 2023Article
- The role of NEDD4 related HECT-type E3 ubiquitin ligases in defective autophagy in cancer cells: molecular mechanisms and therapeutic perspectives.Molecular medicine (Cambridge, Mass.) · 2023Review
- JNK/Itch Axis Mediates the Lipopolysaccharide-Induced Ubiquitin-Proteasome-Dependent Degradation of Ferritin Light Chain in Murine Macrophage Cells.Inflammation · 2022Article
- Epigenetics and genetics of hepatoblastoma: Linkage and treatment.Frontiers in genetics · 2022Review
- Repurposing old drugs as new inhibitors of the ubiquitin-proteasome pathway for cancer treatment.Seminars in cancer biology · 2021Review
- Exosomes Immunity Strategy: A Novel Approach for Ameliorating Intervertebral Disc Degeneration.Frontiers in cell and developmental biology · 2021Review
- Deletion of Wild-type p53 Facilitates Bone Metastatic Function by Blocking the AIP4 Mediated Ligand-Induced Degradation of CXCR4.Frontiers in pharmacology · 2021Article
- ITCH as a potential therapeutic target in human cancers.Seminars in cancer biology · 2020Review
- Itch attenuates CD4 T-cell proliferation in mice by limiting WBP2 protein stability.European journal of immunology · 2020Article
- NORE1A directs apoptotic switch of TNF signaling through reciprocal modulation of ITCH-mediated destruction of TNFRI and BAX.Oncogene · 2020Article
- Aberrant activation of neuronal cell cycle caused by dysregulation of ubiquitin ligase Itch results in neurodegeneration.Cell death & disease · 2020Article
- Functional role of WW domain-containing proteins in tumor biology and diseases: Insight into the role in ubiquitin-proteasome system.FASEB bioAdvances · 2020Article
- Silencing E3 Ubiqutin ligase ITCH as a potential therapy to enhance chemotherapy efficacy in p53 mutant neuroblastoma cells.Scientific reports · 2020Article
- The non-enzymatic RAS effector RASSF7 inhibits oncogenic c-Myc function.The Journal of biological chemistry · 2018Article
- Tumor suppressor C-RASSF proteins.Cellular and molecular life sciences : CMLS · 2018Review
- Ubiquitin-Dependent Regulation of the Mammalian Hippo Pathway: Therapeutic Implications for Cancer.Cancers · 2018Review
- WW-Domain Containing Protein Roles in Breast Tumorigenesis.Frontiers in oncology · 2018Review
- Ras Regulates Rb via NORE1A.The Journal of biological chemistry · 2016Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Ras association (RalGDS/AF-6) domain family member RASSF5 is a non-enzymatic RAS effector super family protein, known to be involved in cell growth regulation. Expression of RASSF5 is found to be extinguished by promoter hypermethylation in different human cancers, and its ectopic expression suppresses cell proliferation and tumorigenicity. Interestingly, this role in tumorigenesis has been confounded by the fact that regulation at molecular level remains unclear and many transformed cells actually display elevated RASSF5 expression. Here, we demonstrate that E3 ubiquitin ligase Itch is a unique binding partner of RASSF5. Itch can interact with PPxY motif in RASSF5 both in vivo and in vitro through its WW domains. Importantly, the overexpression of Itch induces RASSF5 degradation by poly-ubiquitination via 26S proteasome pathway. In addition, our results indicate that the elevated levels of RASSF5 found in tumor cells due to acetylation, which restricts its binding to Itch and results in a more stable inert protein. Inhibition of RASSF5 acetylation permits its interaction with Itch and provokes proteasomal degradation. These data suggest that apart from promoter methylation, hyperacetylation could also be downregulating RASSF5 function in different human cancer. Finally, results from functional assays suggest that the overexpression of wild type, not the ligase activity defective Itch negatively regulate RASSF5-mediated G1 phase transition of cell cycle as well as apoptosis, suggesting that Itch alone is sufficient to alter RASSF5 function. Collectively, the present investigation identifies a HECT class E3 ubiquitin ligase Itch as a unique negative regulator of RASSF5, and suggests the possibility that acetylation as a potential therapeutic target for human cancer.
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