| http://purl.uniprot.org/citations/31097685 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/31097685 | http://www.w3.org/2000/01/rdf-schema#comment | "Clear cell renal cell carcinoma (ccRCC) is the most-prominent tumor type of kidney cancers. Resistance of renal cell carcinoma (RCC) against tumor therapy is often owing to apoptosis resistance, e.g., by overexpression of anti-apoptotic proteins. However, little is known about the role of the apoptosis inhibitor c-FLIP and its potential impact on death receptor-induced apoptosis in ccRCC cells. In this study, we demonstrate that c-FLIP is crucial for resistance against CD95L-induced apoptosis in four ccRCC cell lines. Strikingly, downregulation of c-FLIP expression by short hairpin RNA (shRNA)interference led to spontaneous caspase activation and apoptotic cell death. Of note, knockdown of all c-FLIP splice variants was required to induce apoptosis. Stimulation of ccRCC cells with CD95L induced NF-κB and MAP kinase survival pathways as revealed by phosphorylation of RelA/p65 and Erk1/2. Interestingly, CD95L surface expression was high in all cell lines analyzed, and CD95 but not TNF-R1 clustered at cell contact sites. Downstream of CD95, inhibition of the NF-κB pathway led to spontaneous cell death. Surprisingly, knockdown experiments revealed that c-FLIP inhibits NF-κB activation in the context of CD95 signaling. Thus, c-FLIP inhibits apoptosis and dampens NF-κB downstream of CD95 but allows NF-κB activation to a level sufficient for ccRCC cell survival. In summary, we demonstrate a complex CD95-FLIP-NF-κB-signaling circuit, in which CD95-CD95L interactions mediate a paracrine survival signal in ccRCC cells with c-FLIP and NF-κB both being required for inhibiting cell death and ensuring survival. Our findings might lead to novel therapeutic approaches of RCC by circumventing apoptosis resistance."xsd:string |
| http://purl.uniprot.org/citations/31097685 | http://purl.org/dc/terms/identifier | "doi:10.1038/s41419-019-1609-y"xsd:string |
| http://purl.uniprot.org/citations/31097685 | http://purl.uniprot.org/core/author | "Schmitz I."xsd:string |
| http://purl.uniprot.org/citations/31097685 | http://purl.uniprot.org/core/author | "Schumann S."xsd:string |
| http://purl.uniprot.org/citations/31097685 | http://purl.uniprot.org/core/author | "Luebke T."xsd:string |
| http://purl.uniprot.org/citations/31097685 | http://purl.uniprot.org/core/author | "Schwarz L."xsd:string |
| http://purl.uniprot.org/citations/31097685 | http://purl.uniprot.org/core/author | "Plaza-Sirvent C."xsd:string |
| http://purl.uniprot.org/citations/31097685 | http://purl.uniprot.org/core/author | "Beer Y.Y."xsd:string |
| http://purl.uniprot.org/citations/31097685 | http://purl.uniprot.org/core/author | "Misterek M."xsd:string |
| http://purl.uniprot.org/citations/31097685 | http://purl.uniprot.org/core/author | "Sander F.E."xsd:string |
| http://purl.uniprot.org/citations/31097685 | http://purl.uniprot.org/core/date | "2019"xsd:gYear |
| http://purl.uniprot.org/citations/31097685 | http://purl.uniprot.org/core/name | "Cell Death Dis"xsd:string |
| http://purl.uniprot.org/citations/31097685 | http://purl.uniprot.org/core/pages | "384"xsd:string |
| http://purl.uniprot.org/citations/31097685 | http://purl.uniprot.org/core/title | "c-FLIP and CD95 signaling are essential for survival of renal cell carcinoma."xsd:string |
| http://purl.uniprot.org/citations/31097685 | http://purl.uniprot.org/core/volume | "10"xsd:string |
| http://purl.uniprot.org/citations/31097685 | http://www.w3.org/2004/02/skos/core#exactMatch | http://purl.uniprot.org/pubmed/31097685 |
| http://purl.uniprot.org/citations/31097685 | http://xmlns.com/foaf/0.1/primaryTopicOf | https://pubmed.ncbi.nlm.nih.gov/31097685 |
| http://purl.uniprot.org/uniprot/#_A0A024R3Y4-mappedCitation-31097685 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/31097685 |
| http://purl.uniprot.org/uniprot/#_E9PAP3-mappedCitation-31097685 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/31097685 |
| http://purl.uniprot.org/uniprot/#_A0A336TY74-mappedCitation-31097685 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/31097685 |
| http://purl.uniprot.org/uniprot/#_B4DMB6-mappedCitation-31097685 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/31097685 |
| http://purl.uniprot.org/uniprot/#_B4E361-mappedCitation-31097685 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/31097685 |
| http://purl.uniprot.org/uniprot/#_O15519-mappedCitation-31097685 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/31097685 |
| http://purl.uniprot.org/uniprot/#_Q59F61-mappedCitation-31097685 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/31097685 |