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By revealing how mutations in the HDAC8 gene disrupt the biology of proteins that control both gene expression and cell division, the research sheds light on this disease, which causes intellectual disability, limb deformations and other disabilities resulting from impairments in early development.
The study team found that mutations in the HDAC8 gene threw off normal cellular recycling of cohesin.
Mutations in the gene cause loss of HDAC8 protein activity, and consequently decrease the amount of "recharged" cohesin available to properly regulate gene transcription.
The researchers showed in cell cultures that mutations in HDAC8 lead to a decrease in cohesin binding to genes, similar to that seen for cells deficient in the NIPBL gene.
These studies follow the first report of the crystal structure of the enzyme HDAC8 that was published by Celera Genomics in the journal Structure in July 2004.
The first six targets, which are now undergoing computer modeling, are HDAC8, JAK3, JAK2, PGP, HSP90, and the thioredoxin/glutathione reductase protein from the Schistosoma parasite.
In a second poster entitled "Specific Inhibition of HDAC8 by Antisense Leads to Growth Arrest and Apoptosis of Human Cancer Cells," (poster #1807), MethylGene presented target-validation data showing that specific inhibition of HDAC8 induces growth arrest and apoptosis in human cancer cells but not in normal cells, in a dose-dependent and time-dependent manner.
The HDAC8 structure was determined using Syrrx's Nanovolume Crystallization(R) technology to crystallize disease-associated proteins.
Results from the in-vitro study demonstrate that Pharmacyclics' proprietary HDAC inhibitor, PCI-34051, inhibits HDAC8 with 200-1000 fold selectivity over other HDAC enzymes.
include a description of HDAC8 bound to inhibitors(R) technology to crystallize disease-associated proteins.
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