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http://purl.uniprot.org/citations/33461590http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/33461590http://www.w3.org/2000/01/rdf-schema#comment"

Background

The IκB kinase (IKK) complex, comprising the two enzymes IKKα and IKKβ, is the main activator of the inflammatory transcription factor NF-κB, which is constitutively active in many cancers. While several connections between NF-κB signaling and the oncogene c-Myc have been shown, functional links between the signaling molecules are still poorly studied.

Methods

Molecular interactions were shown by co-immunoprecipitation and FRET microscopy. Phosphorylation of c-Myc was shown by kinases assays and its activity by improved reporter gene systems. CRISPR/Cas9-mediated gene knockout and chemical inhibition were used to block IKK activity. The turnover of c-Myc variants was determined by degradation in presence of cycloheximide and by optical pulse-chase experiments.. Immunofluorescence of mouse prostate tissue and bioinformatics of human datasets were applied to correlate IKKα- and c-Myc levels. Cell proliferation was assessed by EdU incorporation and apoptosis by flow cytometry.

Results

We show that IKKα and IKKβ bind to c-Myc and phosphorylate it at serines 67/71 within a sequence that is highly conserved. Knockout of IKKα decreased c-Myc-activity and increased its T58-phosphorylation, the target site for GSK3β, triggering polyubiquitination and degradation. c-Myc-mutants mimicking IKK-mediated S67/S71-phosphorylation exhibited slower turnover, higher cell proliferation and lower apoptosis, while the opposite was observed for non-phosphorylatable A67/A71-mutants. A significant positive correlation of c-Myc and IKKα levels was noticed in the prostate epithelium of mice and in a variety of human cancers.

Conclusions

Our data imply that IKKα phosphorylates c-Myc on serines-67/71, thereby stabilizing it, leading to increased transcriptional activity, higher proliferation and decreased apoptosis."xsd:string
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http://purl.uniprot.org/citations/33461590http://purl.uniprot.org/core/author"Moser B."xsd:string
http://purl.uniprot.org/citations/33461590http://purl.uniprot.org/core/author"Schmid J.A."xsd:string
http://purl.uniprot.org/citations/33461590http://purl.uniprot.org/core/author"Salzmann M."xsd:string
http://purl.uniprot.org/citations/33461590http://purl.uniprot.org/core/author"Resch U."xsd:string
http://purl.uniprot.org/citations/33461590http://purl.uniprot.org/core/author"Hoesel B."xsd:string
http://purl.uniprot.org/citations/33461590http://purl.uniprot.org/core/author"Basilio J."xsd:string
http://purl.uniprot.org/citations/33461590http://purl.uniprot.org/core/author"Gleitsmann V."xsd:string
http://purl.uniprot.org/citations/33461590http://purl.uniprot.org/core/author"Hochreiter B."xsd:string
http://purl.uniprot.org/citations/33461590http://purl.uniprot.org/core/author"Noreen M."xsd:string
http://purl.uniprot.org/citations/33461590http://purl.uniprot.org/core/author"Panhuber A."xsd:string
http://purl.uniprot.org/citations/33461590http://purl.uniprot.org/core/author"Pardo-Garcia A."xsd:string
http://purl.uniprot.org/citations/33461590http://purl.uniprot.org/core/date"2021"xsd:gYear
http://purl.uniprot.org/citations/33461590http://purl.uniprot.org/core/name"Mol Cancer"xsd:string
http://purl.uniprot.org/citations/33461590http://purl.uniprot.org/core/pages"16"xsd:string
http://purl.uniprot.org/citations/33461590http://purl.uniprot.org/core/title"The inflammatory kinase IKKalpha phosphorylates and stabilizes c-Myc and enhances its activity."xsd:string
http://purl.uniprot.org/citations/33461590http://purl.uniprot.org/core/volume"20"xsd:string
http://purl.uniprot.org/citations/33461590http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/33461590
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