Kinase inhibitors modulate huntingtin cell localization and toxicity - PubMed (original) (raw)

. 2011 May 29;7(7):453-60.

doi: 10.1038/nchembio.582.

Affiliations

• PMID: 21623356
• DOI: 10.1038/nchembio.582

Kinase inhibitors modulate huntingtin cell localization and toxicity

Randy Singh Atwal et al. Nat Chem Biol. 2011.

Abstract

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.

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Comment in

• Huntington's disease: flipping a switch on huntingtin.
  Greiner ER, Yang XW. Greiner ER, et al. Nat Chem Biol. 2011 Jun 17;7(7):412-4. doi: 10.1038/nchembio.604. Nat Chem Biol. 2011. PMID: 21685885 No abstract available.

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