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CCNE1 interactome analysis in HEK293T cells under the treatment of different CCNE1(:CDK2) ligands

ABSTRACT: This is to explore potential functional effects of CCNE1(:CDK2) ligands and compare them side by side.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Yuanjin Zhang

LAB HEAD: Benjamin F. Cravatt

PROVIDER: PXD048328 | Pride | 2024-09-03

REPOSITORIES: Pride

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			Action	DRS
	20230609_Exp388-2_Yuanjin_01.raw	Raw
	20230609_Exp388-2_Yuanjin_02.raw	Raw
	20230609_Exp388-2_Yuanjin_03.raw	Raw
	20230915_Exp396_YZ_01.raw	Raw
	20230915_Exp396_YZ_02.raw	Raw

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1 - 5 of 21

Publications

Expanding the ligandable proteome by paralog hopping with covalent probes.

Zhang Yuanjin Y Liu Zhonglin Z Hirschi Marsha M Brodsky Oleg O Johnson Eric E Won Sang Joon SJ Nagata Asako A Petroski Matthew D MD Majmudar Jaimeen D JD Niessen Sherry S VanArsdale Todd T Gilbert Adam M AM Hayward Matthew M MM Stewart Al E AE Nager Andrew R AR Melillo Bruno B Cravatt Benjamin B

bioRxiv : the preprint server for biology 20240119

More than half of the ~20,000 protein-encoding human genes have at least one paralog. Chemical proteomics has uncovered many electrophile-sensitive cysteines that are exclusive to a subset of paralogous proteins. Here, we explore whether such covalent compound-cysteine interactions can be used to discover ligandable pockets in paralogs that lack the cysteine. Leveraging the covalent ligandability of C109 in the cyclin CCNE2, we mutated the corresponding residue in paralog CCNE1 to cysteine (N112 ...[more]

PMID: 38293178

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Protein-directed ABPP describing proteome-wide reactivities of WX-02-520 and WX-02-521 probes

Project description:More than half of the ∼20,000 protein-encoding human genes have at least one paralog. Chemical proteomics has uncovered many electrophile-sensitive cysteines that are exclusive to a subset of paralogous proteins. Here, we explore whether such covalent compound-cysteine interactions can be used to discover ligandable pockets in paralogs that lack the cysteine. Leveraging the covalent ligandability of C109 in the cyclin CCNE2, we mutated the corresponding residue in paralog CCNE1 to cysteine (N112C) and found through activity-based protein profiling (ABPP) that this mutant reacts stereoselectively and site-specifically with tryptoline acrylamides. We then converted the tryptoline acrylamide-N112C-CCNE1 interaction into a NanoBRET-ABPP assay capable of identifying compounds that reversibly inhibit both N112C- and WT-CCNE1:CDK2 complexes. X-ray crystallography revealed a cryptic allosteric pocket at the CCNE1:CDK2 interface adjacent to N112 that binds the reversible inhibitors. Our findings thus provide a roadmap for leveraging electrophile-cysteine interactions to extend the ligandability of the proteome beyond covalent chemistry.

2024-09-03 | PXD053077 | Pride

Inactivation of CDK2 is synthetic lethal to MYCN-overexpressing cancer cells

Project description:Two genes have a synthetic lethal relationship when silencing or inhibition of one gene is only lethal in the context of a mutation or activation of the second gene. This situation offers an attractive therapeutic strategy, as inhibition of such a gene will only trigger cell death in tumor cells with an activated second oncogene but spare normal cells without activation of the second oncogene. Here we present evidence that CDK2 is synthetic lethal to neuroblastoma cells with MYCN amplification and overexpression. Neuroblastomas are childhood tumors with an often lethal outcome. Twenty percent of the tumors have MYCN amplification and these tumors are ultimately refractory to any therapy. Targeted silencing of CDK2 by three RNA interference techniques induced apoptosis in MYCN-amplified neuroblastoma cell lines, but not in MYCN single copy cells. Silencing of MYCN abrogated this apoptotic response in MYCN-amplified cells. Inversely, silencing of CDK2 in MYCN single copy cells did not trigger apoptosis, unless a MYCN transgene was activated. The MYCN induced apoptosis after CDK2 silencing was accompanied by nuclear stabilization of P53 and mRNA profiling showed up-regulation of P53 target genes. Silencing of P53 rescued the cells from MYCN-driven apoptosis. The synthetic lethality of CDK2 silencing in MYCN activated neuroblastoma cells can also be triggered by inhibition of CDK2 with a small molecule drug. Treatment of neuroblastoma cells with Roscovitine, a CDK inhibitor, at clinically achievable concentrations induced MYCN-dependent apoptosis. The synthetic lethal relation between CDK2 and MYCN indicates CDK2 inhibitors as potential MYCN-selective cancer therapeutics. CDK2 shRNA in a tet repressor system was stably transfected in the IMR32 cell line. Time course analysis was performed in triplicate after induction of CDK2 shRNA at 5 time points.

2014-05-19 | E-GEOD-16480 | biostudies-arrayexpress

CDK2 depletion effect on human myeloid cell line undergoing differentiation

Project description:Analysis of NB4 myeloid cells depleted for CDK2. Results provide insight into the role of CDK2 in myeloid cell differentiation. We used microarrays to detail the global programme of gene expression underlying CDK2-depletion induced differentiation and identified distinct classes of up-regulated genes during this process.

2018-12-31 | GSE64077 | GEO

Inactivation of CDK2 is synthetic lethal to MYCN-overexpressing cancer cells

2014-05-19 | GSE16480 | GEO

Human HCT-116 cells: Control vs CDK2 knockout, NU6102 treated and resistant cells

Project description:Transcriptional profiling of isogenic human colorectal cancer cell line HCT-116, comparing parental cells, CDK2 knockout cells, cells treated with the CDK2-selective inhibitor NU6102 and cells resistant to 50µM NU6102. The aim was to compare effects of loss of CDK2 gene or kinase activity and determine potential mechanisms of inhibitor-resistance

2017-08-03 | GSE102165 | GEO

Halolamina pelagica strain:CDK2

Project description:Halolamina pelagica strain:CDK2 Genome sequencing and assembly

| PRJNA272888 | ENA

Transcriptomic expression of A549 CDK2 KO cells treated or untreated with palbociclib

Project description:Inducing senescence in cancer cells is emerging as a new therapeutic strategy. We tested the senescence induction of palbociclib in CDK2 KO cells, and profiled these for senescence associated gene signatures. This was a CRISPR generated CDK2 KO clone in A549 cells.

2022-03-03 | GSE197600 | GEO

Copy number analysis of OVCAR-3 and CDK2 resistant sublines

Project description:Cyclin E1 (CCNE1) is amplified in various tumor types including high-grade serous ovarian cancer where it is associated with poor clinical outcome. We have demonstrate that suppression of the Cyclin E1 partner kinase, CDK2, induces apoptosis in a CCNE1 amplicon-dependent manner. Little is known of mechanisms of resistance to CDK inhibitors. We therefore generated OVCAR-3 sublines with reduced sensitivity to CDK2 inhibitors and profiled by SNP copy number microarrays. Arrayed samples included parental OVCAR-3 cells and five independently derived sublines resistant to PHA-533533 (OVCAR3-533533-R1, -R3, -R5, -R6, -R7). The resistant cell lines were arrayed after drug selection (P5).

2013-09-01 | E-GEOD-48920 | biostudies-arrayexpress

Gene expression analysis of OVCAR-3 and CDK2 resistant sublines

2013-09-01 | GSE48919 | GEO

Gene expression analysis of OVCAR-3 and CDK2 resistant sublines

Project description:Cyclin E1 (CCNE1) is amplified in various tumor types including high-grade serous ovarian cancer where it is associated with poor clinical outcome. We have demonstrate that suppression of the Cyclin E1 partner kinase, CDK2, induces apoptosis in a CCNE1 amplicon-dependent manner. Little is known of mechanisms of resistance to CDK inhibitors. We therefore generated OVCAR-3 sublines with reduced sensitivity to CDK2 inhibitors and profiled by gene expression microarrays. Arrayed samples included parental OVCAR-3 cells (n = 4 replicates) and five independently derived sublines resistant to PHA-533533 (OVCAR3-533533-R1, -R3, -R5, -R6, -R7). The resistant cell lines were arrayed after drug selection (P5) and after continued passage in the absence of inhibitor (P10+).

2013-09-01 | E-GEOD-48919 | biostudies-arrayexpress

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