Selective inhibition of CDK7 reveals the influence of CDK7 on psoriatic CD4+ T cells
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ABSTRACT:
PROVIDER: PRJNA720557 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14181755_1.fastq.gz | Fastqsanger.gz | |||
| SRR14181755_2.fastq.gz | Fastqsanger.gz | |||
| SRR14181756_1.fastq.gz | Fastqsanger.gz | |||
| SRR14181756_2.fastq.gz | Fastqsanger.gz | |||
| SRR14181757_1.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: The goals of this study are to compare the differential gene of psoriatic CD4+ T cells treated with THZ1 and DMSO Methods: RNA sequencing of psoriatic CD4+ T cells which treated with THZ1 (10 nM) or DMSO
2021-04-09 | GSE171676 | GEO
Project description:Cyclin-dependent kinase 7 (CDK7) plays a critical role in the general regulation of RNA polymerase II-mediated transcription. However, the absence of selective CDK7 inhibitors has hindered the ability to investigate the consequences of acute and prolonged inhibition of CDK7 under normal and pathological conditions. Here we present the discovery and characterization of the first covalent CDK7 inhibitor, CDK7-IN-1, that has the unprecedented ability to target a unique cysteine residue located outside of the canonical kinase domain, providing an unanticipated means of achieving selectivity for CDK7 amongst the 20 known CDKs. Cancer cell line profiling indicates that a subset of cancer cell lines, including T-cell acute lymphoblastic leukemia (T-ALL), exhibit 100-fold greater sensitivity to CDK7-IN-1 over other tumor and normal cell lines. Genome-wide expression analysis in Jurkat T-ALL indicates that CDK7-IN-1 disproportionally affects RUNX1 as well as other components of the TAL1 transcriptional network and its targets, downregulating key regulators of transcription and apoptosis critical for the T-ALL state. These oncogenes are encoded by short-lived mRNA transcripts, are associated with super-enhancers, and exhibit a strong dependency on continuous transcription for sustained expression. Therefore, pharmacological modulation of CDK7 kinase activity may define a method for the identification and treatment of tumor types exhibiting extreme dependencies on transcription for maintenance of the oncogenic state. Jurkat, MM1S, Loucy, and HeLa (WT and Dox-inducible CDK7 mutant) cells were treated with various drugs including a covalent inhibitor of CDK7 (CDK7-IN-1), a reversible inhibitor of CDK7 (CDK7-IN-1), Flavopiridol, Actinomycin D, and DMSO controls. Replicates are annotated.
2014-06-22 | E-GEOD-50624 | biostudies-arrayexpress
Project description:The aim of the study was to compare the transcriptional profile of healthy skin Tregs to Tregs isolated from psoriatic lesions and to compare these profiles to CD4 Teffectors isolated from the same patient.
2019-11-08 | GSE139341 | GEO
Project description:Cyclin-dependent kinase 7 (CDK7) plays a critical role in the general regulation of RNA polymerase II-mediated transcription. However, the absence of selective CDK7 inhibitors has hindered the ability to investigate the consequences of acute and prolonged inhibition of CDK7 under normal and pathological conditions. Here we present the discovery and characterization of the first covalent CDK7 inhibitor, CDK7-IN-1, that has the unprecedented ability to target a unique cysteine residue located outside of the canonical kinase domain, providing an unanticipated means of achieving selectivity for CDK7 amongst the 20 known CDKs. Cancer cell line profiling indicates that a subset of cancer cell lines, including T-cell acute lymphoblastic leukemia (T-ALL), exhibit 100-fold greater sensitivity to CDK7-IN-1 over other tumor and normal cell lines. Genome-wide expression analysis in Jurkat T-ALL indicates that CDK7-IN-1 disproportionally affects RUNX1 as well as other components of the TAL1 transcriptional network and its targets, downregulating key regulators of transcription and apoptosis critical for the T-ALL state. These oncogenes are encoded by short-lived mRNA transcripts, are associated with super-enhancers, and exhibit a strong dependency on continuous transcription for sustained expression. Therefore, pharmacological modulation of CDK7 kinase activity may define a method for the identification and treatment of tumor types exhibiting extreme dependencies on transcription for maintenance of the oncogenic state. Jurkat cells were treated with various drugs including a covalent inhibitor of CDK7 (CDK7-IN-1), a reversible inhibitor of CDK7 (CDK7-IN-1), Flavopiridol, Actinomycin D, and DMSO controls. Replicates are annotated.
2013-12-23 | E-GEOD-50622 | biostudies-arrayexpress
Project description:Purpose: Resistance to endocrine therapy (ET) and CDK4/6 inhibitors (CDK4/6i) is a clinical challenge in estrogen receptor (ER) positive (ER+) breast cancer (BC). Cyclin-dependent kinase 7 (CDK7) is a candidate target in endocrine resistant ER+ BC models and selective CDK7 inhibitors (CDK7i) are in clinical development for the treatment of ER+ BC. Nonetheless, the precise mechanisms responsible for the activity of CDK7i in ER+ BC remain elusive. Herein, we sought to unravel these mechanisms. Experimental Design: We conducted multi-omic analyses in ER+ BC models in vitro and in vivo including models with different genetic backgrounds. We also performed genome wide CRISPR knock-out library screens to identify potential therapeutic vulnerabilities in CDK4/6i resistance models. Results: We found that the on-target anti-tumor effects of CDK7 inhibition in ER+ BC are in part p53 dependent, involve cell-cycle inhibition and suppression of c-Myc. Moreover, CDK7 inhibition exhibited cytotoxic effects, distinctive from the cytostatic nature of ETs and CDK4/6i. CDK7 inhibition resulted in suppression of ER phosphorylation at S118, however, long-term CDK7 inhibition resulted in increased ER signaling, supporting the combination of ET with a CDK7i. Lastly, genome wide CRISPR/Cas9 screens identified CDK7 and MYC signaling as putative vulnerabilities in CDK4/6i resistance, and CDK7 inhibition effectively inhibited CDK4/6i resistant models. Conclusions: Taken together, these findings support the clinical investigation of selective CDK7 inhibition combined with ET to overcome treatment resistance in ER+ BC. In addition, our study highlights the potential of increased c-Myc activity and intact p53 as predictors for sensitivity to CDK7 inhibitor-based treatments.
2024-02-12 | GSE230362 | GEO
Project description:CDK7 associates with the 10-subunit TFIIH complex and regulates transcription by phosphorylating the C-terminal domain (CTD) of RNA polymerase II (RNAPII). Few additional CDK7 substrates are known. Here, using the covalent inhibitor SY-351 and quantitative phosphoproteomics, we identified CDK7 kinase substrates in human cells. Among hundreds of high-confidence targets, the vast majority are unique to CDK7 (i.e. distinct from other transcription-associated kinases), with a subset that suggest novel cellular functions. Transcription-associated factors were predominant CDK7 substrates, including SF3B1, U2AF2, and other splicing components. Accordingly, widespread and diverse splicing defects, such as alternative exon inclusion and intron retention, were characterized in CDK7-inhibited cells. Combined with biochemical assays, we establish that CDK7 directly activates other transcription-associated kinases CDK9, CDK12, and CDK13, invoking a “master regulator” role in transcription. We further demonstrate that TFIIH restricts CDK7 kinase function to the RNAPII CTD, whereas other substrates (e.g. SPT5, SF3B1) are phosphorylated by the 3-subunit CDK-activating kinase (CAK; CCNH, MAT1, CDK7). These results suggest new models for CDK7 function in transcription and implicate CAK dissociation from TFIIH as essential for kinase activation. This straightforward regulatory strategy ensures CDK7 activation is spatially and temporally linked to transcription, and may apply toward other transcription-associated kinases.
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Project description:Transcriptional profiling of primary Cdk7lox/lox MEFs comparing Adeno-Cre vs Adeno-GFP infected controls. Samples were obtained 7 days after the Adeno-Cre mediated elimination of Cdk7. Goal was to determine the effects of Cdk7 elimination on RNA polII-mediated transcription. Two-condition experiment, Adeno-Cre vs. Adeno-GFP infected Cdk7lox/lox MEFs. Biological replicates: 10 independent primary MEF preparations.
2012-04-17 | E-GEOD-36050 | biostudies-arrayexpress
Project description:Psoriatic arthritis is a seronegative polyarticular form of inflammatory arthritis . Genetic analysis implicates a role for both IL-17/23 axis and CD8+ T cells in disease susceptibility. Using RNA-seq we identified differential gene expression between synovial IL-17A+(IFNy+/-) CD8+ T cells compared to IL-17A-IFNy+ CD8+ T cells and IL-17A+CD4+ T cells from the synovial fluid of psoriatic arthritis patients. We find that IL-17A+CD8+ T cells have a transcriptional overlap with IL-17A+CD4+ T cells. Overall we show these IL-17A+ CD8+ T cells have a polyfunctional, pro-inflammatory capacity and are potentially derived from common precursors, shared with IL-17A-CD8+ T cells.
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Project description:Cdk7, the CDK-activating kinase and transcription factor IIH component, is a target of inhibitors that kill cancer cells by exploiting tumor-specific transcriptional dependencies. However, whereas selective inhibition of analog-sensitive (AS) Cdk7 in colon cancer derived cells arrests division and disrupts transcription, it does not by itself trigger apoptosis efficiently. Here we show that p53 activation by 5-fluorouracil or nutlin-3 synergizes with a reversible Cdk7as inhibitor to induce cell death. Synthetic lethality was recapitulated with covalent inhibitors of wild-type Cdk7, THZ1 or the more selective YKL-1-116. The effects were allele-specific; a CDK7as mutation conferred both sensitivity to bulky adenine analogs and resistance to covalent inhibitors. Non-transformed colon epithelial cells were resistant to these combinations, as were cancer-derived cells with p53-inactivating mutations. Apoptosis was dependent on death receptor DR5, a p53 transcriptional target whose expression was refractory to Cdk7 inhibition. Therefore, p53 activation induces transcriptional dependency to sensitize cancer cells to Cdk7 inhibition.
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Project description:Development of a selective CDK7 covalent inhibitor reveals predominant cell cycle phenotype
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