A20 regulates canonical wnt-signaling through an interaction with RIPK4
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA435878 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6781160.fastq.gz | Fastqsanger.gz | |||
| SRR6781170.fastq.gz | Fastqsanger.gz | |||
| SRR6781161.fastq.gz | Fastqsanger.gz | |||
| SRR6781171.fastq.gz | Fastqsanger.gz | |||
| SRR6781162.fastq.gz | Fastqsanger.gz |
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Project description:The role of A20 in regulating canonical wnt signaling was investigated in colon cancer cell lines (RKO) by RNAseq
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Project description:A20 is a ubiquitin-editing enzyme that is known to regulate inflammatory signaling and cell death. However, A20 mutations are also frequently found in multiple malignancies suggesting a potential role as a tumor suppressor as well. We recently described a novel role for A20 in regulating the wnt-beta-catenin signaling pathway and suppressing colonic tumor development in mice. The underlying mechanisms for this phenomenon are unclear. To study this, we first generated A20 knockout cell lines by genome-editing techniques. Using these cells, we show that loss of A20 causes dysregulation of wnt-dependent gene expression by RNAseq. Mechanistically, A20 interacts with a proximal signaling component of the wnt-signaling pathway, receptor interacting protein kinase 4 (RIPK4), and regulation of wnt-signaling by A20 occurs through RIPK4. Finally, similar to the mechanism by which A20 regulates other members of the receptor interacting protein kinase family, A20 modifies ubiquitin chains on RIPK4 suggesting a possible molecular mechanism for A20's control over the wnt-signaling pathway.
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Project description:The receptor-interacting protein kinase 4 (RIPK4) plays an oncogenic role in melanoma by regulating NFκB and Wnt/β-catenin pathways. As its role in melanoma remains not fully understood, we examined the effects of its downregulation on melanoma transcriptomics. Using RNA-seq, we observed broad transcriptome changes in WM266.4 cells upon RIPK4 downregulation, indicating a complex role for RIPK4 in regulating adhesion, migration, proliferation, and inflammatory processes in melanoma cells. Furthermore, our study highlights the potential functional partners of RIPK4, such as BIRC3, TNF-α receptors, and MAP2K6.
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Project description:The function of the FAM83F protein, like the functions of many members of the FAM83 family, is poorly understood. Here we show that injection of Fam83f mRNA into Xenopus embryos causes axis duplication, a phenotype indicative of enhanced Wnt signalling. Consistent with this, overexpression of FAM83F activates Wnt signalling, whilst ablation of FAM83F from human colorectal cancer (CRC) cells attenuates it. We demonstrate that FAM83F is farnesylated and interacts and co-localises with CK1α at the plasma membrane. This interaction with CK1α is essential for FAM83F to activate Wnt signalling, and FAM83F mutants that do not interact with CK1α fail to induce axis duplication in Xenopus embryos and to activate Wnt signalling in cells. FAM83F acts upstream of GSK-3β, because the attenuation of Wnt signalling caused by loss of FAM83F can be rescued by GSK-3 inhibition. Introduction of a farnesyl-deficient mutant of FAM83F in cells through CRISPR/Cas9 genome editing redirects the FAM83F-CK1α complex away from the plasma membrane and significantly attenuates Wnt signalling, indicating that FAM83F exerts its effects on Wnt signalling at the plasma membrane.
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Project description:A20 is known key regulator of NF-κB activity and inflammatory response, but its role in the control of cell death receptor signaling is not completely understood. Although A20 is widely accepted anti-apoptotic protein, we demonstrate that elevated expression of A20 in both, human and murine keratinocytes results in sensitisation to TNF-induced cell death. We prove that the Ripoptosome formation in A20 overexpressing cells is prerequisite for the TNF-induced cell death execution. We demonstrate that both canonical and non-canonical NF-κB signaling pathways are regulated upon increase of A20 expression. A20 dependent alteration of cIAPs and TRAF1 expressions are involved in the multiple level control of cell death in keratinocytes with elevated A20 expression.
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Project description:A20 is known key regulator of NF-κB activity and inflammatory response, but its role in the control of cell death receptor signaling is not completely understood. Although A20 is widely accepted anti-apoptotic protein, we demonstrate that elevated expression of A20 in both, human and murine keratinocytes results in sensitisation to TNF-induced cell death. We prove that the Ripoptosome formation in A20 overexpressing cells is prerequisite for the TNF-induced cell death execution. We demonstrate that both canonical and non-canonical NF-κB signaling pathways are regulated upon increase of A20 expression. A20 dependent alteration of cIAPs and TRAF1 expressions are involved in the multiple level control of cell death in keratinocytes with elevated A20 expression.
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Project description:Up-regulation of canonical Wnt signaling has been implicated in liver fibrosis and cancer. To determine canonical Wnt target genes potentially implicated in these diseases, we performed microarray analysis of culture-activated rat hepatic stellate cells (HSCs) treated with canonical Wnt inhibitors, DKK-1, ICG-001, or FJ9.
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Project description:RIPK4 but not the related kinases RIPK1, RIPK2, and RIPK3 caused similar transcriptional changes to Wnt3a. PA1 cells were transfected by 8ug RIPK1, RIPK2, RIPK3, or RIPK4 for 48h, RNA were extracted and sequenced.
2013-02-04 | E-GEOD-43362 | biostudies-arrayexpress
Project description:One of the most critical axes for cell fate determination is how cells respond to excessive reactive oxygen species (ROS)-oxidative stress. Extensive lipid peroxidation commits cells to death via a distinct cell death paradigm termed ferroptosis. However, the molecular mechanism regulating cellular fates to distinct ROS remains incompletely understood. Through siRNA against human receptor-interacting protein kinases (RIPK) family members, we discovered that RIPK4 is crucial for oxidative stress and ferroptotic death. Upon ROS induction, RIPK4 is rapidly activated and the kinase activity of RIPK4 is indispensable to induce cell death. Specific ablation of RIPK4 in kidney proximal tubules protects mice from acute kidney injury induced by cisplatin and renal ischemia/reperfusion. RNA sequencing revealed the dramatically decreased expression of acyl-CoA synthetase medium-chain (ACSM) family members induced by cisplatin treatment which is compromised in RIPK4 deficient mice. Among these ACSM family members, suppression of ACSM1 strongly augments oxidative stress and ferroptotic cell death with induced expression of ACSL4, an important component for ferroptosis execution. Our lipidome analysis revealed that over-expression of ACSM1 leads to the accumulation of monounsaturated fatty acids (MUFAs), attenuation of polyunsaturated fatty acids (PUFAs) production, and thereby cellular resistance to ferroptosis. Hence, knock-down ACSM1 re-sensitizes RIPK4 KO cells to oxidative stress and ferroptotic death. In conclusion, RIPK4 is a key player involved in oxidative stress and ferroptotic death, which is potentially important for a broad spectrum of human pathologies. The link between RIPK4-ASCM1 axis to PUFAs and ferroptosis reveals a novel mechanism to oxidative stress induced necrosis and ferroptosis.
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