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The involvement of RIPK4 in TNF-α-stimulated IL-6 and IL-8 production by melanoma cells

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE263112 | GEO | 2024/04/27

REPOSITORIES: GEO

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The involvement of RIPK4 in TNF-α-stimulated IL-6 and IL-8 production by melanoma cells

Project description:The involvement of RIPK4 in TNF-α-stimulated IL-6 and IL-8 production by melanoma cells

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RIPK4 promotes oxidative stress and ferroptotic death through the downregulation of ACSM1

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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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

RNAseq E15.5 mouse skin WT, Irf6 KO, Ripk4 KD, and Irf6 S413A.S424A knockin

Project description:The integrity of the mammalian epidermis is essential for organism survival, and it depends on a balance of proliferation and differentiation in the resident stem cell population. The kinase Ripk4 and the transcription factor Irf6 are mutated in severe developmental syndromes in humans, and mice lacking these genes display epidermal hyperproliferation and soft tissue fusions, resulting in neonatal lethality. However, the mechanism by which these genes control epidermal differentiation in vivo is unknown. By generating various mouse knock-out and knock-in strains we demonstrate that in vivo the role of Ripk4 in development is dependent on its kinase activity, Ripk4 and Irf6 function cell autonomously in the epidermis,Ripk4 and Irf6 lie on a linear pathway and phosphorylation of Irf6 on Serine413 and Serine424 is essential to prime it for activation. This priming then allows Ripk4 to phosphorylate Irf6 on Serine90, which ensures Irf6 activation. We then use RNA-seq, ChIP-seq and ATAC-seq analysis to define the global transcriptional targets of Irf6 in epidermal differentiation. Collectively, our results explain how Ripk4 activates Irf6, and how this pathway ensures epidermal differentiation and a functional barrier. This is crucial for understanding the etiology of developmental syndromes that are characterized by orofacial, skin and genital abnormalities.

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Transcriptional profiles of PA1 teratoma cells transfected by RIPK1, RIPK2, RIPK3, or RIPK4

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The involvement of RIPK4 in TNF-α-stimulated IL-6 and IL-8 production by melanoma cells.

Project description:PurposeThe receptor-interacting protein kinase (RIPK4) has an oncogenic function in melanoma, regulates NF-κB and Wnt/β-catenin pathways, and is sensitive to the BRAF inhibitors: vemurafenib and dabrafenib which lead to its decreased level. As its role in melanoma remains not fully understood, we examined the effects of its downregulation on the transcriptomic profile of melanoma.MethodsApplying RNA-seq, we revealed global alterations in the transcriptome of WM266.4 cells with RIPK4 silencing. Functional partners of RIPK4 were evaluated using STRING and GeneMANIA databases. Cells with transient knockdown (via siRNA) and stable knockout (via CRISPR/Cas9) of RIPK4 were stimulated with TNF-α. The expression levels of selected proteins were assessed using Western blot, ELISA, and qPCR.ResultsGlobal analysis of gene expression changes indicates a complex role for RIPK4 in regulating adhesion, migration, proliferation, and inflammatory processes in melanoma cells. Our study highlights potential functional partners of RIPK4 such as BIRC3, TNF-α receptors, and MAP2K6. Data from RIPK4 knockout cells suggest a putative role for RIPK4 in modulating TNF-α-induced production of IL-8 and IL-6 through two distinct signaling pathways-BIRC3/NF-κB and p38/MAPK. Furthermore, increased serum TNF-α levels and the correlation of RIPK4 with NF-κB were revealed in melanoma patients.ConclusionThese data reveal a complex role for RIPK4 in regulating the immune signaling network in melanoma cells and suggest that this kinase may represent an alternative target for melanoma-targeted adjuvant therapy.

| S-EPMC11043103 | biostudies-literature

RIPK4 promotes oxidative stress and ferroptotic death through the downregulation of ACSM1

Project description:RIPK4 promotes oxidative stress and ferroptotic death through the downregulation of ACSM1

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Project description:In this study, we found that RIPK4 protein driven by TP53 mutation is highly expressed in CRC, which can promote the phosphorylation level of MTHFD1 (Methylenetetrahydrofolate Dehydrogenase, Cyclohydrolase And Formyltetrahydrofolate Synthetase 1), a key enzyme of carbon metabolism, promote the generation of NADPH in CRC cells, and reduce the level of ROS, thus promoting PANoptosis resistance and distant metastasis of CRC cells. We explain the novel mechanism of metastasis induced by the TP53 mutation in terms of post-translational modification and clarify the biological role of the RIPK4 protein in CRC, which can be used as a new target for the treatment of metastatic CRC.

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RIPK4 driven by TP53 mutations promotes resistance to PANoptosis and metastasis of CRC by phosphorylation of MTHFD1 [RIPK4_sh_seq]

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Project description:Global studies on the role of RIPK4 in melanoma.

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