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Ser46 phosphorylation and prolyl-isomerase Pin1-mediated isomerization of p53 are key events in p53-dependent apoptosis induced by mutant huntingtin
Alice Grison, Fiamma Mantovani, Anna Comel, Elena Agostoni, Stefano Gustincich, Francesca Persichetti and Giannino Del Sal
Proceedings of the National Academy of Sciences of the United States of America
Vol. 108, No. 44 (November 1, 2011), pp. 17979-17984
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/41352638
Page Count: 6
You can always find the topics here!Topics: Neurons, Apoptosis, Phosphorylation, Proteins, DNA damage, Huntington disease, Gene expression regulation, Isomerization, Brain, Mice
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Huntington disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the gene coding for huntingtin protein. Several mechanisms have been proposed by which mutant huntingtin (mHtt) may trigger striatal neurodegeneration, including mitochondrial dysfunction, oxidative stress, and apoptosis. Furthermore, mHtt induces DNA damage and activates a stress response. In this context, p53 plays a crucial role in mediating mHtt toxic effects. Here we have dissected the pathway of p53 activation by mHtt in human neuronal cells and in HD mice, with the aim of highlighting critical nodes that may be pharmacologically manipulated for therapeutic intervention. We demonstrate that expression of mHtt causes increased phosphorylation of p53 on Ser46, leading to its interaction with phosphorylation-dependent prolyl isomerase Pin1 and consequent dissociation from the apoptosis inhibitor iASPP, thereby inducing the expression of apoptotic target genes. Inhibition of Ser46 phosphorylation by targeting homeodomain-interacting protein kinase 2 (HIPK2), PKCδ, or ataxia telangiectasia mutated kinase, as well as inhibition of the prolyl isomerase Pin1, prevents mHttdependent apoptosis of neuronal cells. These results provide a rationale for the use of small-molecule inhibitors of stress-responsive protein kinases and Pin1 as a potential therapeutic strategy for HD treatment.
Proceedings of the National Academy of Sciences of the United States of America © 2011 National Academy of Sciences