Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

RNA-Seq identifies alternative splicing of CRBN induced by ILF3 KO

ABSTRACT: We present a first-in-class GSPT1-selective CELMoD, CC-90009, which is currently in a phase 1 clinical trial for the treatment of relapsed or refractory (R/R) AML (CC-90009-AML-001; NCT02848001). Biochemical, structural and molecular characterization supports that CC-90009 coopts the CUL4-DDB1-CRBN-RBX1 (CRL4-CRBN) E3 ubiquitin ligase complex to selectively target GSPT1 for ubiquitination and proteasomal degradation, culminating in rapid induction of apoptosis and growth inhibition in AML cell lines and patient leukemic blasts. Knockout of ILF2/ILF3 decreased the production of full-length CRBN transcript via modulating CRBN mRNA alternative splicing, leading to significant downregulation of cereblon expression and hence diminished response to CC-90009.

ORGANISM(S): Homo sapiens

PROVIDER: GSE154257 | GEO | 2021/02/05

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

CRL4(CRBN) ubiquitin ligase profiling

Project description:In the 1950s the drug thalidomide administered as a sedative to pregnant women led ot the birth of thousands of children with multiple defects. Despite its teratogenicity, thalidomide and ist IMiD derivatives recently emerged as effective treatments for multiple myeloma and 5q-dysplasia. IMiDs target the CUL4-RBX1-DDB1-CRBN (CRL4(CRBN)) ubiquitin ligase. Through an unbiased screen we identify the homeobox trranscription factor MEIS2 as an endogenous substrate of CRL4(CRBN). By definition, a specific target of CRL4(CRBN) is expected to have a very low intensity on negative control arrays (E1_E2), (E1_CRBN), (E1_E2_Cdt2), (E1_E2_Cdt2_revlimid), (E1_E2_Cdt2_CSN) or with CRL4(CRBN) in presence of inhibitor (E1_E2_CRBN_revlimid) and high intensity on arrays with CRL4(CRBN) (E1_E2_CRBN) or CRL4(CRBN) in presence of CSN (E1_E2_CRBN_CSN) Accordingly 16 protein microarrays were subjected to in vitro ubiquitylation using the following enzyme combinations: 3x Uba1+UbcH5a; 2x Uba1+UbcH5a+CRL4(DDB2); 3x Uba1+UbcH5a+CRL4(CRBN); 2x Uba1+UbcH5a+CRL4(CRBN)+lenalidomide; 2x Uba1+UbcH5a+CRL4(CRBN)+CSN; 2x Uba1+UbcH5a+CRL4(Cdt2); 1x Uba1+UbcH5a+CRL4(Cdt2)+CSN; 1x Uba1+UbcH5a+CRL4(Cdt2)+lenalidomide

2014-05-13 | E-GEOD-57554 | biostudies-arrayexpress

CRL4(CRBN) ubiquitin ligase profiling

2014-05-13 | GSE57554 | GEO

Expression data from comparison of wild type and cereblon knock out murine T-cells

Project description:Thalidomide and other immunomodulatory drugs are effective therapies for certain hematological cancers where they kill tumor cells and stimulate T-cell immunity. These compounds mediate their functions by binding to and altering substrate specificity of cereblon (CRBN), an E3-ubiquitin ligase component of the DDB1/Cul4/Rbx1 complex3-5. Here, we report the results of crbn genetic deficiency in a mouse, which revealed CRBN functions as a suppressor of T-cell receptor (TCR) activation. We used microarrays to analyze the cereblon regulated gene expression changes following activation of wild type or cereblon knock out murine T-cells.

2020-05-06 | GSE81725 | GEO

Deciphering the Mechanisms of CC-122 Resistance in DLBCL via a Genome-Wide Screen

Project description:CC-122 is a next-generation cereblon E3 ligase modulating agent that has demonstrated promising clinical efficacy in relapsed or refractory diffuse large B‐cell lymphoma (R/R DLBCL) patients. Mechanistically, CC-122 induces the degradation of IKZF1/3, leading to T cell activation and robust cell-autonomous killing in DLBCL. Here, we report a genome-wide CRISPR/Cas9 positive selection screen for CC-122 in a DLBCL cell line SU-DHL-4 with follow-up mechanistic characterization in 6 DLBCL cell lines to identify genes regulating the response to CC-122. Top-ranked CC-122 resistance genes encode not only well-defined members or regulators of the CUL4-DDB1-RBX1-CRBN E3 ubiquitin ligase complex, but also key components of several signaling and transcriptional networks that have not previously been shown to modulate the response to other cereblon modulators. Ablation of CYLD, NFKBIA, TRAF2, or TRAF3 induces hyper-activation of the canonical and/or non-canonical NF-κB pathways and subsequently diminishes CC-122-induced apoptosis in 5 out of 6 DLBCL cell lines. Depletion of KCTD5, the substrate receptor of the CUL3-RBX1-KCTD5 ubiquitin ligase complex, promotes the stabilization of its cognate substrate, GNG5, resulting in CC-122 resistance in HT, SU-DHL-4, and WSU-DLCL2. Furthermore, knockout of AMBRA1 renders resistance to CC-122 in SU-DHL-4 and U-2932, whereas knockout of RFX7 leads to resistance specifically in SU-DHL-4. The ubiquitous and cell line-specific mechanisms of CC-122 resistance in DLBCL cell lines revealed in this work pinpoint genetic alternations that are potentially associated with clinical resistance in patients, and facilitate the development of biomarker strategies for patient stratification, which may improve clinical outcome of CC-122 for R/R DLBCL.

2020-10-01 | GSE158303 | GEO

Homo sapiens

Project description:CRL4(CRBN) ubiquitin ligase profiling

| PRJNA246700 | ENA

pSILAC mass spectrometry reveals ZFP91 as novel IMiD dependent substrate of the CRL4CRBN ligase

Project description:Thalidomide and its derivatives lenalidomide and pomalidomide (IMiDs) are effective treatments of hematologic malignancies. It was shown that IMiDs impart gain of function properties to the CUL4-RBX1-DDB1-CRBN (CRL4CRBN) ubiquitin ligase that enable binding, ubiquitination and degradation of key therapeutic targets such as IKFZ1, IKZF3 and CSNK1A1. While these substrates have been implicated as efficacy targets in multiple myeloma (MM) and 5q deletion associated myelodysplastic syndrome (del(5q)-MDS), other targets likely exist. Using a pulse-chase SILAC mass spectrometry-based proteomics approach, we demonstrate that lenalidomide induces the ubiquitination and degradation of ZFP91. We establish that ZFP91 is a bona fide IMiD dependent CRL4CRBN substrate and further show that ZFP91 harbors a zinc finger (ZnF) motif, related to the IKZF1/3 ZnF, critical for IMiD dependent CRBN binding. These findings demonstrate that single time point pulse-chase SILAC mass spectrometry-based proteomics (pSILAC-MS) is a sensitive approach for target identification of small molecules inducing selective protein degradation.

2017-03-01 | GSE94728 | GEO

Knockdown of ILF2/ILF3 (NF45/NF90) in the gastric cancer cell line SGC7901

Project description:Our data showed that lncRNA ELF3-AS1 could bind on the exon1 of ELF3-201 to form a double-stranded RNA molecule. This double-stranded RNA could interact with ILF2/ILF3 complex. To explore the biofunction of the interaction between ELF3-AS1 and ILF2/ILF3 complex, loss-of-function studies regarding ILF2 and ILF3 were performed in SGC7901 cell line. RNA sequencing studies showed that knockdown of ILF3 significantly decreased ELF3-AS1, while knockdown of ILF2 significantly increased ELF3-AS1 and NF90 expression. Our data revealed that ILF2/ILF3 complex interacted with ELF3-AS1/ELF3 double-stranded RNA and regulated their transcripts stability.

2021-10-01 | GSE161544 | GEO

Transcriptome and analysis of Wdr70 deletion by next-generation sequencing

Project description:CRL4 is a family of SCF-like ubiquitin ligase constituted by Cul4-Ddb1-RING finger scaffold and DCAF substrate adaptors. We revealed Wdr70 as a novel DCAF protein that assembles with Cul4-Ddb1 and functions as chromatin remodeling factor in Schizosaccharomyces pombe.Besides its function in DNA repair, CRL4Wdr70 is speculated to regulate gene expression in a subset of yeast transcriptome. Here we use the next-generation sequencing to show that deletion of Wdr70 gene disturbs the gene expression profile of G2-synchronised yeast cells. Examination of genome-wide gene expression in 2 different yeast strains using Illumina Hiseq2500.

2016-04-04 | E-GEOD-79830 | biostudies-arrayexpress

TMT analysis of MOLM-13 cells treated with SJ001007095

Project description:Targeted Protein Degradation (TPD) encompasses two approaches that generate small molecules with similar proteasome-dependent mechanisms of action: Proteolysis-Targeting Chimeras (PROTACs) and Molecular Glues (MGs). Our goal is to develop novel MG approaches that exploit the E3 ubiquitin ligase Cereblon (CRBN) to degrade key oncogenic drivers in the leading causes of childhood cancer death: acute myeloid leukemia (AML). This project will identify new vulnerabilities and compounds that degrade hitherto undruggable transcription factors in high-risk acute leukemia (AL) and medulloblastoma (MB). Based on our preliminary data, we hypothesize that compound SJ001007095 targets AML cells independent of GSPT1 degradation. Our aims are to understand the mechanism by which compound SJ001007095 targets AML cells using TMT proteomic approach and identify proteins targeted by the compound SJ001007095 leading to their degradation and consequently AML cell death.

2023-12-01 | PXD045170 | Pride

A Novel Cereblon Modulator Targets eRF3 Family Proteins For Cereblon-dependent Destruction

Project description:To discern why GSPT1 depletion induced growth inhibition, we utilized RNA microarray analysis to profile the transcriptional changes in cells treated with CC-885 or DMSO. To discern why CC-885 induced growth inhibition, we utilized RNA microarray analysis to profile the transcriptional changes in cells treated with CC-885 or DMSO Several key markers of the ATF4 pathway including ATF3, CHOP (DDIT3), and ATF4 were significantly induced by CC-885 treatment.

2018-12-17 | GSE76195 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

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