Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Targeted Degradation of CDK9 Potently Disrupts MYC Network

ABSTRACT: Cyclin-dependent kinase 9 (CDK9) coordinates signaling events that regulate RNA polymerase II (Pol II) pause-release states. It is an important co-factor for transcription factors, such as MYC, that drive aberrant cell proliferation when their expression is deregulated. CDK9 modulation offers an approach for attenuating dysregulation in such transcriptional programs. As a result, numerous drug development campaigns to inhibit CDK9 kinase activity have been pursued. We validated that CDK9 inhibition triggers a compensatory mechanism that dampens its effect on MYC transcriptional programs and found that this resistance mechanism was absent when the Kinase is degraded. Importantly, CDK9 degradation is more effective than its inhibition for disrupting MYC transcriptional regulatory circuitry likely through the abrogation of both enzymatic and scaffolding functions of CDK9.

ORGANISM(S): Homo sapiens

PROVIDER: GSE263153 | GEO | 2025/05/07

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Expression profiling of HeLa cell line treated with CDK9 inhibitor

Project description:CDK9 is the kinase subunit of P-TEFb that enables RNA polymerase (Pol) II to transit from promoter-proximal pausing to productive elongation. Although considerable interest exists in CDK9 as a therapeutic target, little progress has been made due to the lack of highly selective inhibitors. Here, we describe the development of i-CDK9 as such an inhibitor that potently suppresses CDK9 phosphorylation of substrates and causes genome-wide Pol II pausing. While most genes experience reduced expression, MYC and other primary response genes increase expression upon sustained i-CDK9 treatment. Essential for this increase, the bromodomain protein BRD4 captures P-TEFb from 7SK snRNP to deliver to target genes and also enhances CDK9’s activity and resistance to inhibition. Because the i-CDK9-induced MYC expression and binding to P-TEFb compensate for P-TEFb’s loss of activity, only the simultaneous inhibition of CDK9 and MYC can efficiently induce growth arrest and apoptosis of cancer cells, suggesting the potential of a combinatorial treatment strategy. We used microarrays to examine the global impact on gene expression by imhibiting CDK9 at different time durations. HeLa cell lines treated with CDK9 inhibitor at different time points

2015-06-17 | E-GEOD-60952 | biostudies-arrayexpress

Compensatory induction of MYC expression by sustained CDK9 inhibition via a BRD4-dependent mechanism: Pol II occupancy profiling by ChIP-Seq in HeLa cell line in the presence or absence of CDK9 inhibition

Project description:CDK9 is the kinase subunit of P-TEFb that enables RNA polymerase (Pol) II to transit from promoter-proximal pausing to productive elongation. Although considerable interest exists in CDK9 as a therapeutic target, little progress has been made due to the lack of highly selective inhibitors. Here, we describe the development of i-CDK9 as such an inhibitor that potently suppresses CDK9 phosphorylation of substrates and causes genome-wide Pol II pausing. While most genes experience reduced expression, MYC and other primary response genes increase expression upon sustained i-CDK9 treatment. Essential for this increase, the bromodomain protein BRD4 captures P-TEFb from 7SK snRNP to deliver to target genes and also enhances CDK9’s activity and resistance to inhibition. Because the i-CDK9-induced MYC expression and binding to P-TEFb compensate for P-TEFb’s loss of activity, only the simultaneous inhibition of CDK9 and MYC can efficiently induce growth arrest and apoptosis of cancer cells, suggesting the potential of a combinatorial treatment strategy. ChIP-seq of Pol II in HeLa cells before or after i-CDk9 treatment

2015-06-17 | E-GEOD-60953 | biostudies-arrayexpress

Expression profiling of HeLa cell line treated with CDK9 inhibitor

2015-06-17 | GSE60952 | GEO

2015-06-17 | GSE60953 | GEO

Selective inhibition of CDK9 in triple negative breast cancer

Project description:Targeted treatment for triple-negative breast cancer (TNBC) remains an elusive clinical challenge. Cyclin-dependent kinase 9 (CDK9) is a transcriptional regulator shown to promote growth of multiple cancers, including TNBC, and represents a potential new therapeutic target. CDK9 increases RNA Polymerase II (Pol II) activity, which facilitates sustained expression of short-lived oncogenic and anti-apoptotic proteins. However, pre-clinical evaluation of CDK9 as a therapeutic target has been hampered by the poor selectivity of existing CDK9 inhibitors (CDK9i). Here, we report a novel CDK9i; D11-8, which exhibits high potency against CDK9 (Ki = 8 nM) and displays remarkable selectivity over other CDKs and human kinases. D11-8 inhibited TNBC cell line proliferation,, induced G2/M cell cycle arrest, and increased apoptosis. Mechanistically, D11-8 inhibited CDK9; reducing Pol II phosphorylation, down-regulating expression of proto-oncogene MYC and anti-apoptotic marker MCL1, and dramatically inducing Pol II promoter-proximal pausing at MYC, G2/M checkpoint, and E2F2 target genes. D11-8 was further validated for TNBC in vivo, and inhibited TNBC cell line tumour growth without toxicity. To further elucidate the cancer cell specificity of D11-8, normal breast tissue was collected from women undergoing reduction mammoplasty surgery and treated with D11-8 ex vivo as patient-derived explants. High doses of D11-8 (2.7 µM) had no effect on the proliferative capacity of normal breast epithelial cells (Ki67 positivity), and tissues appeared histologically normal. Collectively, these data demonstrate that D11-8 effectively inhibits CDK9 in TNBC cell lines, resulting in growth inhibition without short-term toxicity.

2023-11-25 | GSE184335 | GEO

Targeted Degradation of CDK9 Potently Disrupts MYC Network

Project description:Targeted Degradation of CDK9 Potently Disrupts MYC Network

| PRJNA1095987 | ENA

The NELF pausing checkpoint mediates the functional divergence of Cdk9

Project description:Cdk9 is an essential transcriptional kinase that is conserved across distant eukaryotes, but we previously found that acute inhibition of Cdk9 causes different transcriptional phenotypes in NELF-containing higher eukaryotes (like mammals and Drosophila) vs. the NELF-lacking fission yeast S. pombe. NELF is known to participate in promoter-proximal pausing of RNA Polymerase II, and using NELF-depleted Drosophila cells, we find that this NELF-mediated pause is necessary to prevent gene body entry by Pol II in the absence of Cdk9. Without NELF, the abnormal gene body entry that occurs following Cdk9 inhibition is strikingly similar to that seen in S. pombe, and in either case, these Pol II complexes have elongation defects and are unable to complete gene transcription. These results show that NELF enforces an early checkpoint for Cdk9 and efficiently shuts down gene transcription in its absence. We propose this would have been critical for the emergence of gene regulatory strategies acting via Cdk9 to modulate transcription of specific genes.

2023-03-22 | GSE211397 | GEO

Ant-leukemic effect of CDK9 inhibition in T-cell prolymphocytic leukemia (mRNA)

Project description:We investigated the pharmacological effects of the novel highly specific cyclin-dependent kinase 9 (CDK9) inhibitor LDC526 and its clinically used derivate atuveciclib employing primary T-PLL cells in an ex vivo drug sensitivity testing platform. All T-PLL samples were sensitive to CDK9 inhibition at submicromolar concentrations while conventional cytotoxic drugs were found to be largely ineffective. At the cellular level LDC526 inhibited the phosphorylation at serine 2 of the RNA polymerase II C-terminal domain resulting in decreased de novo RNA transcription. LDC526 induced apoptotic leukemic cell death through down-regulating MYC and MCL1 both at the mRNA and protein level. Microarray based transcriptomic profiling revealed that genes down-modulated in response to CDK9 inhibition were enriched for MYC and JAK-STAT targets. By contrast, CDK9 inhibition increased the expression of the tumor suppressor FBXW7 which may contribute to decreased MYC and MCL1 protein levels. The combination of atuvecliclib and the BCL2 inhibitor venetoclax exhibited synergistic anti-leukemic activity, providing the rationale for a novel targeted-agent based treatment of T-PLL.

2020-11-02 | GSE155747 | GEO

Ant-leukemic effect of CDK9 inhibition in T-cell prolymphocytic leukemia (microRNA)

2020-11-02 | GSE155746 | GEO

Identification of CDK9 targets using DRB and quantitative phosphoproteomics

Project description:CDK9 is a critical kinase required for the productive transcription of protein-coding genes by RNA polymerase II (pol II) in higher eukaryotes. Phosphorylation of targets including the elongation factor SPT5 and the carboxyl-terminal domain (CTD) of RNA pol II allow the polymerase to pass an early elongation checkpoint (EEC), which is encountered soon after initiation. In addition to halting RNA polymerase II at the EEC, CDK9 inhibition also causes premature termination of transcription across the last exon, loss of polyadenylation factors from chromatin, and loss of polyadenylation of nascent transcripts. Inhibition of the phosphatase PP2A abrogates the premature termination and loss of polyadenylation caused by CDK9 inhibition, suggesting that CDK9 and PP2A, working together, regulate the coupling of elongation and transcription termination to RNA maturation. Our phosphoproteomic analyses, using either DRB or an analog-sensitive CDK9 cell line confirm the splicing factor SF3B1 as an additional key target of this kinase. CDK9 inhibition causes loss of interaction of splicing and export factors with SF3B1, suggesting that CDK9 also helps to co-ordinates coupling of splicing and export to transcription.

2022-08-22 | PXD026720 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data