Kinase inhibitors modulate huntingtin cell localization and toxicity
| Autor: | Randy Singh Atwal, Ray Truant, Jianrun Xia, Carly R. Desmond, Simonetta Sipione, Tamara Maiuri, Nicholas S. Caron |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
congenital
hereditary and neonatal diseases and abnormalities Huntingtin Cell Survival Blotting Western Fluorescent Antibody Technique Nerve Tissue Proteins Spindle Apparatus Biology Endoplasmic Reticulum Transfection Cell Line Mice mental disorders Genetic model Huntingtin Protein Serine Animals ASK1 Phosphorylation Casein Kinase II Molecular Biology Protein Kinase Inhibitors Cell Nucleus Kinase Cyclin-dependent kinase 2 Nuclear Proteins Cell Biology Subcellular localization Molecular biology nervous system diseases I-kappa B Kinase Disease Models Animal Huntington Disease nervous system Mutation biology.protein |
| Zdroj: | Nature chemical biology. 7(7) |
| ISSN: | 1552-4469 |
| Popis: | Two serine residues within the first 17 amino acid residues of huntingtin (N17) are crucial for modulation of mutant huntingtin toxicity in cell and mouse genetic models of Huntington's disease. Here we show that the stress-dependent phosphorylation of huntingtin at Ser13 and Ser16 affects N17 conformation and targets full-length huntingtin to chromatin-dependent subregions of the nucleus, the mitotic spindle and cleavage furrow during cell division. Polyglutamine-expanded mutant huntingtin is hypophosphorylated in N17 in both homozygous and heterozygous cell contexts. By high-content screening in live cells, we identified kinase inhibitors that modulated N17 phosphorylation and hence huntingtin subcellular localization. N17 phosphorylation was reduced by casein kinase-2 inhibitors. Paradoxically, IKKβ kinase inhibition increased N17 phosphorylation, affecting huntingtin nuclear and subnuclear localization. These data indicate that huntingtin phosphorylation at Ser13 and Ser16 can be modulated by small-molecule drugs, which may have therapeutic potential in Huntington's disease. |
| Databáze: | OpenAIRE |
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