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The inflammatory kinase IKKα phosphorylates and stabilizes c-Myc and enhances its activity.

Abstract：

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.

journal_name

Mol Cancer

journal_title

Molecular cancer

authors

Moser B,Hochreiter B,Basílio J,Gleitsmann V,Panhuber A,Pardo-Garcia A,Hoesel B,Salzmann M,Resch U,Noreen M,Schmid JA

doi

10.1186/s12943-021-01308-8

subject

Has Abstract

pub_date

2021-01-18 00:00:00

pages

issue

issn

1476-4598

pii

10.1186/s12943-021-01308-8

journal_volume

pub_type

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The inflammatory kinase IKKα phosphorylates and stabilizes c-Myc and enhances its activity.