Journal
NUCLEIC ACIDS RESEARCH
Volume 47, Issue 9, Pages 4476-4494Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkz163
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Funding
- Cancer Research UK [C1506/A11643, C8820/A19062]
- Biotechnology and Biological Sciences Research Council [BB/F000340/1]
- Breast Cancer Campaign [2006NovPHD13]
- Wellcome Trust [Z06343/Z/17/Z]
- School of Pharmacy
- Qalaa Holdings (Egypt) Scholarship
- School of Pharmacy, University of Nottingham
- BBSRC [BB/F000340/1] Funding Source: UKRI
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IRF1 (Interferon Regulatory Factor-1) is the prototype of the IRF family of DNA binding transcription factors. IRF1 protein expression is regulated by transient up regulation in response to external stimuli followed by rapid degradation via the ubiquitin-proteasome system. Here we report that DNA bound IRF1 turnover is promoted by GSK3 beta (Glycogen Synthase Kinase 3 beta) via phosphorylation of the T181 residue which generates a phosphodegron for the SCF (Skp-Cul-Fbox) ubiquitin E3-ligase receptor protein Fbxw7 alpha (F-box/WD40 7). This regulated turnover is essential for IRF1 activity, as mutation of T181 results in an improperly stabilized protein that accumulates at target promoters but fails to induce RNA-Pol-II elongation and subsequent transcription of target genes. Consequently, the anti-proliferative activity of IRF1 is lost in cell lines expressing T181A mutant. Further, cell lines with dysfunctional Fbxw7 are less sensitive to IRF1 overexpression, suggesting an important co-activator function for this ligase complex. As T181 phosphorylation requires both DNA binding and RNA-Pol-II elongation, we propose that this event acts to clear 'spent' molecules of IRF1 from transcriptionally engaged target promoters.
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