Relocalizing transcriptional kinases to activate apoptosis.

in Science (New York, N.Y.) by Roman C Sarott, Sai Gourisankar, Basel Karim, Sabin Nettles, Haopeng Yang, Brendan G Dwyer, Juste M Simanauskaite, Jason Tse, Hind Abuzaid, Andrey Krokhotin, Tinghu Zhang, Stephen M Hinshaw, Michael R Green, Gerald R Crabtree, Nathanael S Gray

TLDR

  • The study found that kinase inhibitors can be used to activate specific genes in cells. The researchers made a special kind of molecule that could bring two different things together, and when they did, it made the cells produce a protein that killed them. This could be useful for treating diseases where the cells are not producing enough of this protein.

Abstract

Kinases are critical regulators of cellular function that are commonly implicated in the mechanisms underlying disease. Most drugs that target kinases are molecules that inhibit their catalytic activity, but here we used chemically induced proximity to convert kinase inhibitors into activators of therapeutic genes. We synthesized bivalent molecules that link ligands of the transcription factor B cell lymphoma 6 (BCL6) to inhibitors of cyclin-dependent kinases (CDKs). These molecules relocalized CDK9 to BCL6-bound DNA and directed phosphorylation of RNA polymerase II. The resulting expression of pro-apoptotic, BCL6-target genes caused killing of diffuse large B cell lymphoma cells and specific ablation of the BCL6-regulated germinal center response. Genomics and proteomics corroborated a gain-of-function mechanism in which global kinase activity was not inhibited but rather redirected. Thus, kinase inhibitors can be used to context-specifically activate transcription.

Overview

  • The study investigates the use of chemically induced proximity to convert kinase inhibitors into activators of therapeutic genes. The researchers synthesized bivalent molecules that link ligands of the transcription factor B cell lymphoma 6 (BCL6) to inhibitors of cyclin-dependent kinases (CDKs). These molecules relocalized CDK9 to BCL6-bound DNA and directed phosphorylation of RNA polymerase II. The resulting expression of pro-apoptotic, BCL6-target genes caused killing of diffuse large B cell lymphoma cells and specific ablation of the BCL6-regulated germinal center response. The study aims to demonstrate that kinase inhibitors can be used to context-specifically activate transcription.
  • Methodology and Subject Demographics:
  • The study used bivalent molecules that link ligands of the transcription factor B cell lymphoma 6 (BCL6) to inhibitors of cyclin-dependent kinases (CDKs). These molecules were tested on diffuse large B cell lymphoma cells. The study did not provide information on subject demographics.
  • Primary Objective:
  • The primary objective of the study is to demonstrate that kinase inhibitors can be used to context-specifically activate transcription.

Comparative Analysis & Findings

  • The study compared the outcomes observed under different experimental conditions. The results showed that the bivalent molecules relocalized CDK9 to BCL6-bound DNA and directed phosphorylation of RNA polymerase II. The resulting expression of pro-apoptotic, BCL6-target genes caused killing of diffuse large B cell lymphoma cells and specific ablation of the BCL6-regulated germinal center response. The study found that kinase inhibitors can be used to context-specifically activate transcription.
  • Key Findings:
  • The key findings of the study are that the bivalent molecules relocalized CDK9 to BCL6-bound DNA and directed phosphorylation of RNA polymerase II. The resulting expression of pro-apoptotic, BCL6-target genes caused killing of diffuse large B cell lymphoma cells and specific ablation of the BCL6-regulated germinal center response. The study also found that kinase inhibitors can be used to context-specifically activate transcription.
  • Significance of Findings:
  • The study's findings demonstrate that kinase inhibitors can be used to context-specifically activate transcription. This could have significant implications for the development of new therapies for diseases that involve dysregulation of kinase activity.

Implications and Future Directions

  • The study's findings suggest that kinase inhibitors can be used to context-specifically activate transcription. This could have significant implications for the development of new therapies for diseases that involve dysregulation of kinase activity. However, the study did not provide information on the long-term effects of using kinase inhibitors in this way. Future research should investigate the long-term effects of using kinase inhibitors to context-specifically activate transcription.
  • Limitations of the Study:
  • The study did not provide information on the long-term effects of using kinase inhibitors in this way. Additionally, the study only tested the bivalent molecules on diffuse large B cell lymphoma cells, and further research is needed to determine the generalizability of the findings.
  • Future Research Directions:
  • Future research should investigate the long-term effects of using kinase inhibitors to context-specifically activate transcription. Additionally, further research is needed to determine the generalizability of the findings and to test the bivalent molecules on other cell types and diseases.
  • TLDR:
  • The study demonstrates that kinase inhibitors can be used to context-specifically activate transcription. The bivalent molecules relocalized CDK9 to BCL6-bound DNA and directed phosphorylation of RNA polymerase II. The resulting expression of pro-apoptotic, BCL6-target genes caused killing of diffuse large B cell lymphoma cells and specific ablation of the BCL6-regulated germinal center response. The study's findings suggest that kinase inhibitors can be used to context-specifically activate transcription, which could have significant implications for the development of new therapies for diseases that involve dysregulation of kinase activity.
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