Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 286, Issue 1, Pages 607-619Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M110.153122
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Funding
- Cancer Research UK [C377/A6355]
- Scottish University
- Internal Grant Agency of the Ministry of Health [MZ CR NS/9812-4]
- Grantova Agentura Ceske Republiky [301/08/1468]
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Characteristically for a regulatory protein, the IRF-1 tumor suppressor turns over rapidly with a half-life of between 20-40 min. This allows IRF-1 to reach new steady state protein levels swiftly in response to changing environmental conditions. Whereas CHIP ( C terminus of Hsc70-interacting protein), appears to chaperone IRF-1 in unstressed cells, formation of a stable IRF-1.CHIP complex is seen under specific stress conditions. Complex formation, in heat- or heavy metal-treated cells, is accompanied by a decrease in IRF-1 steady state levels and an increase in IRF-1 ubiquitination. CHIP binds directly to an intrinsically disordered domain in the central region of IRF-1 ( residues 106-140), and this site is sufficient to form a stable complex with CHIP in cells and to compete in trans with full-length IRF-1, leading to a reduction in its ubiquitination. The study reveals a complex relationship between CHIP and IRF-1 and highlights the role that direct binding or docking of CHIP to its substrate(s) can play in its mechanism of action as an E3 ligase.
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