Mediator kinase inhibition suppresses hyperactive interferon signaling in Down syndrome I
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ABSTRACT:
PROVIDER: PRJNA1049467 | ENA |
REPOSITORIES: ENA
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Project description:Mediator kinase inhibition suppresses hyperactive interferon signaling in Down syndrome
| PRJNA910594 | ENA
Project description:Mediator kinase inhibition suppresses hyperactive interferon signaling in Down syndrome II
| PRJNA1049466 | ENA
Project description:Individuals with Down syndrome have a increased likelihood of suffering from inflammatory and autoimmune conditions, due to the presence of four interferon receptors on chromosome 21. Transcription of genes plays a key role in the interferon response, and the Mediator kinases, CDK8 and CDK19, are essential in potentiating this transcription. Given the role CDK8/19 play in the interferon response, and the fact that selective inhibitors of these kinases exist (such as Cortistatin A), it is possible that targetting Mediator kinase activity may alleviate symptoms of chronic inflammation in Down syndrome.
2023-09-12 | GSE220652 | GEO
Project description:Individuals with Down syndrome have a increased likelihood of suffering from inflammatory and autoimmune conditions, due to the presence of four interferon receptors on chromosome 21. Transcription of genes plays a key role in the interferon response, and the Mediator kinases, CDK8 and CDK19, are essential in potentiating this transcription. Given the role CDK8/19 play in the interferon response, and the fact that selective inhibitors of these kinases exist (such as Cortistatin A), it is possible that targetting Mediator kinase activity may alleviate symptoms of chronic inflammation in Down syndrome.
2024-09-01 | GSE249549 | GEO
Project description:Individuals with Down syndrome have a increased likelihood of suffering from inflammatory and autoimmune conditions, due to the presence of four interferon receptors on chromosome 21. Transcription of genes plays a key role in the interferon response, and the Mediator kinases, CDK8 and CDK19, are essential in potentiating this transcription. Given the role CDK8/19 play in the interferon response, and the fact that selective inhibitors of these kinases exist (such as Cortistatin A), it is possible that targetting Mediator kinase activity may alleviate symptoms of chronic inflammation in Down syndrome.
2025-01-01 | GSE249548 | GEO
Project description:MYC-driven medulloblastoma (MB) is a highly aggressive cancer type with poor prognosis and limited treatment options. Through CRISPR-Cas9 screening of MB cell lines, we identified the Mediator-associated kinase CDK8 as a critical regulator of MYC-driven MB. Loss of CDK8 substantially reduces MYC expression, induces pronounced transcriptional changes, suppresses monosome assembly, and decreases ribosome biogenesis and protein synthesis, consequently inhibiting MB growth. Mechanistically, CDK8 regulates the occupancy of RNA polymerase II at specific chromatin loci, facilitating an epigenetic alteration that promotes the transcriptional regulation of ribosomal genes. Targeting CDK8 effectively diminishes the stem-like neoplastic cells characterized by hyperactive ribosome biogenesis. Furthermore, we demonstrated that the combined inhibition of CDK8 and mTOR synergizes to optimize therapeutic outcomes in vivo and in vivo. Overall, our findings establish a connection between CDK8-mediated transcriptional regulation and mRNA translation, suggesting a promising new therapeutic approach that targets the protein synthesis for MYC-driven MB.
2024-12-01 | GSE280973 | GEO
Project description:LNK (SH2B3) is a key negative regulator of JAK-STAT signaling which has been extensively studied in malignant hematopoietic diseases. We found that LNK is significantly elevated in cutaneous melanoma; this elevation is correlated with hyperactive signaling of the RAS-RAF-MEK pathway. Elevated LNK enhances cell growth and survival in adverse conditions. Forced expression of LNK inhibits signaling by interferon-STAT1 and suppresses interferon (IFN) induced cell cycle arrest and cell apoptosis. In contrast, silencing LNK expression by either shRNA or CRISPR-Cas9 potentiates the killing effect of IFN. The IFN-LNK signaling is tightly regulated by a negative feedback mechanism; melanoma cells exposed to IFN upregulate expression of LNK to prevent overactivation of this signaling pathway. Our study reveals an unappreciated function of LNK in melanoma and highlights the critical role of the IFN-STAT1-LNK signaling axis in this potentially devastating disease. LNK may be further explored as a potential therapeutic target for melanoma immunotherapy.
2019-04-29 | GSE127333 | GEO
Project description:LNK (SH2B3) is a key negative regulator of JAK-STAT signaling which has been extensively studied in malignant hematopoietic diseases. We found that LNK is significantly elevated in cutaneous melanoma; this elevation is correlated with hyperactive signaling of the RAS-RAF-MEK pathway. Elevated LNK enhances cell growth and survival in adverse conditions. Forced expression of LNK inhibits signaling by interferon-STAT1 and suppresses interferon (IFN) induced cell cycle arrest and cell apoptosis. In contrast, silencing LNK expression by either shRNA or CRISPR-Cas9 potentiates the killing effect of IFN. The IFN-LNK signaling is tightly regulated by a negative feedback mechanism; melanoma cells exposed to IFN upregulate expression of LNK to prevent overactivation of this signaling pathway. Our study reveals an unappreciated function of LNK in melanoma and highlights the critical role of the IFN-STAT1-LNK signaling axis in this potentially devastating disease. LNK may be further explored as a potential therapeutic target for melanoma immunotherapy.
2019-03-31 | GSE127764 | GEO
Project description:Transcriptional responses to interferon require Mediator kinase-dependent pause release and mechanistically distinct functions of CDK8 and CDK19.
2019-07-15 | GSE129501 | GEO
Project description:Cyclin Dependent Kinases CDK8 and CDK19 (Mediator kinase) are regulatory components of the Mediator complex, a highly conserved complex that fine tunes transcriptional output. While Mediator kinase has been implicated in the transcriptional control of key pathways necessary for development and growth, its function in vivo has not been well described. Herein, we report the consequences of complete ablation of both Cdk8/19 on tissue homeostasis. We show that intestinal epithelial specific deletion of Mediator kinase leads to a distinct defect in secretory progenitor differentiation with broad loss of the intestinal secretory cell types. Using a phospho-proteogenomic approach, we show that the Cdk8/19 kinase module interacts with and phosphorylates components of the chromatin remodeling complex Swi/Snf in intestinal epithelial cells. Genomic localisation of Swi/Snf and Mediator shows Cdk8/19-dependent genomic binding at distinct super-enhancer loci within key lineage specification genes, including the master regulator of secretory differentiation ATOH1. Using CRISPRi/CRISPRa, we identify a distinct Mediator- Swi/Snf bound enhancer element that is necessary and sufficient for ATOH1 expression in a Mediator-kinase dependent manner. As such, these studies uncover a newly described transcriptional mechanism of ATOH1-dependent intestinal cell specification that is dependent on the coordinated interaction of the chromatin remodeling complex Swi/Snf and Mediator complex.
2023-03-10 | PXD030212 | Pride