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NSM00158 Specifically Disrupts the CtBP2-p300 Interaction to Reverse CtBP2-Mediated Transrepression and Prevent the Occurrence of Nonunion. | LitMetric

AI Article Synopsis

  • Carboxyl-terminal binding proteins (CtBPs) are key regulators of gene expression, and their overexpression can lead to issues like atrophic nonunion by repressing important bone development genes.
  • The study focused on a small molecule, NSM00158, which effectively disrupts the interaction between CtBP2 and p300, leading to the disassembly of their associated transcriptional complex.
  • In mouse models, treatment with NSM00158 was shown to prevent nonunion by promoting the upregulation of Runx2's downstream targets, indicating its potential as a therapeutic compound.

Article Abstract

Carboxyl-terminal binding proteins (CtBPs) are transcription regulators that control gene expression in multiple cellular processes. Our recent findings indicated that overexpression of caused the repression of multiple bone development and differentiation genes, resulting in atrophic nonunion. Therefore, disrupting the CtBP2-associated transcriptional complex with small molecules may be an effective strategy to prevent nonunion. In the present study, we developed an screening system in yeast cells to identify small molecules capable of disrupting the CtBP2-p300 interaction. Herein, we focus our studies on revealing the and effects of a small molecule NSM00158, which showed the strongest inhibition of the CtBP2-p300 interaction . Our results indicated that NSM00158 could specifically disrupt CtBP2 function and cause the disassociation of the CtBP2-p300-Runx2 complex. The impairment of this complex led to failed binding of Runx2 to its downstream targets, causing their upregulation. Using a mouse fracture model, we evaluated the effect of NSM00158 on preventing nonunion. Consistent with the results, the NSM00158 treatment resulted in the upregulation of Runx2 downstream targets. Importantly, we found that the administration of NSM00158 could prevent the occurrence of nonunion. Our results suggest that NSM00158 represents a new potential compound to prevent the occurrence of nonunion by disrupting CtBP2 function and impairing the assembly of the CtBP2-p300-Runx2 transcriptional complex.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332362PMC
http://dx.doi.org/10.14348/molcells.2020.0042DOI Listing

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