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Borrowing Transcriptional Kinases to Activate Apoptosis [RNA-seq]

ABSTRACT: Borrowing Transcriptional Kinases to Activate Apoptosis [RNA-seq]

PROVIDER: PRJNA1029048 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26411900_1.fastq.gz	Fastqsanger.gz
	SRR26411900_2.fastq.gz	Fastqsanger.gz
	SRR26411901_1.fastq.gz	Fastqsanger.gz
	SRR26411901_2.fastq.gz	Fastqsanger.gz
	SRR26411902_1.fastq.gz	Fastqsanger.gz

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Borrowing Transcriptional Kinases to Activate Apoptosis [RNA-seq]

Project description:Protein kinases are disease drivers whose therapeutic targeting traditionally centers on inhibition of enzymatic activity. Here chemically induced proximity is leveraged to convert kinase inhibitors into context-specific activators of therapeutic genes. Bivalent molecules that link ligands of the transcription factor B-cell lymphoma 6 (BCL6) to ATP-competitive inhibitors of cyclin-dependent kinases (CDKs) are developed to re-localize CDK to BCL6-bound loci on chromatin and direct phosphorylation of Pol II. The resulting BCL6-target proapoptotic gene expression translates into killing of diffuse large B-cell lymphoma (DLBCL) cells at 72h with EC50s of 0.9 – 10nM and specific ablation of the BCL6-dependent germinal center response in mice. The molecules exhibit 10,000-fold lower cytotoxicity in normal lymphocytes and are well tolerated in mice. Genomic and proteomic evidence corroborate a gain-of-function mechanism where, instead of global enzyme inhibition, a fraction of total kinase activity is borrowed and re-localized to BCL6-bound loci. The strategy demonstrates how kinase inhibitors can be used to context-specifically activate transcription, accessing new therapeutic space.

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Relocalizing transcriptional kinases to activate apoptosis_Proteomics Data

Project description: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. This PRIDE entry contains the raw proteomics data and DIA-NN search output.

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Relocalizing transcriptional kinases to activate apoptosis

Project description:This SuperSeries is composed of the SubSeries listed below.

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ChIP-seq of cyclin-dependent kinases

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