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In Vivo CRISPR Screens Identify E3 Ligase Cop1 as a Modulator of Macrophage Infiltration and Cancer Immunotherapy Target

ABSTRACT: In Vivo CRISPR Screens Identify E3 Ligase Cop1 as a Modulator of Macrophage Infiltration and Cancer Immunotherapy Target

PROVIDER: PRJNA732072 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14624293_1.fastq.gz	Fastqsanger.gz
	SRR14624293_2.fastq.gz	Fastqsanger.gz
	SRR14624294_1.fastq.gz	Fastqsanger.gz
	SRR14624294_2.fastq.gz	Fastqsanger.gz
	SRR14624295_1.fastq.gz	Fastqsanger.gz

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Role of the COP1 E3 ligase in ERalpha signaling

Project description:Our study defines the E3 ligase COP1 as a positive modulator of ERalpha-dependent gene transcription. We carried our RNA-Seq experiments with total RNAs from control or COP1-depleted MCF7 cells treated or not with estrogens and identified a signature of genes known to be regulated by estrogens whose transcription is deregulated upon COP1 deficiency.

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Role of the COP1 E3 ligase in ERalpha signaling

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In Vivo CRISPR Screens Identify E3 Ligase Cop1 as a Modulator of Macrophage Infiltration and Cancer Immunotherapy Target

Project description:Cop1 regulates stability of transcription factors. We found that Cop1 can regulate the proteasomal degradation of Cebpd. We generated 4T1 breast cancer cells with CRISPR/Cas9 mediated Cop1 (gene symbol RFWD2) knockout. We used Cebpd antibody to pulldown the DNA fragments binding with Cebpd and did ChIP-seq.

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A novel Cereblon E3 ligase modulator with antitumor activity in gastrointestinal cancer

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Transcriptomic profiling of Cop1-deficient embryos

Project description:In order to assess the physiological role of Cop1 in vivo we generated mice that do no longer express the protein. Cop1KO mice die at around E10.5 of embryonic development. In order to gain insights into the molecular mechanisms that cause the embryonic death we compared the genome-wide gene expression profile of E9.5 wild-tytpe and Cop1-null embryos. The data do not support a role for Cop1 in the regulation of the p53 pathway in vivo and highlight a role for Cop1 in cardiovascular development and/or angiogenesis. The abstract of the associated publication is as follows:Biochemical data have suggested conflicting roles for the E3 ubiquitin ligase Cop1 in tumourigenesis. Here we present the first in vivo investigation of the role of Cop1 in cancer aetiology. We used an innovative genetic approach to generate an allelic series of Cop1 and show that Cop1 hypomorphic mice spontaneously develop malignancy at a high frequency in their first year of life and are highly susceptible to radiation-induced lymphomagenesis. Biochemically, we show that Cop1 regulates c-Jun oncoprotein stability and modulates c-Jun/AP1 transcriptional activity in vivo. Cop1-deficiency stimulates cell proliferation in a c-Jun-dependent manner. We conclude that Cop1 is a tumour suppressor that antagonizes c-Jun oncogenic activity in vivo. RNA from 6 different control embryos (+/+ or +/-) were mixed and subdivided into control pool 1 and pool 2. RNA from 6 different Cop-null embryos were mixed and subdivided into KO pool 1 and pool 2.

2011-01-13 | E-GEOD-18636 | biostudies-arrayexpress

Ubiquitin ligase COP1 suppresses microglia-mediated inflammation

Project description:Ubiquitin ligase COP1 suppresses microglia-mediated inflammation

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Ubiquitin ligase COP1 suppresses microglia-mediated inflammation

Project description:Dysregulated microglia are intimately involved in neurodegeneration including Alzheimer’s disease (AD) pathogenesis, but the mechanisms controlling pathogenic microglial gene expression remain poorly understood. The transcription factor CCAAT/enhancer binding protein beta (c/EBPß) regulates pro-inflammatory genes in microglia and is upregulated in AD. We show expression of c/EBPß in microglia is regulated post-translationally by the ubiquitin ligase COP1 (also called RFWD2). Ubiquitination of c/EBPß by COP1 targets it for proteasomal degradation. In the absence of COP1, c/EBPß accumulates rapidly and drives a potent pro-inflammatory and ApoE gene-expression program, evidenced by increased neurotoxicity in microglia-neuronal co-cultures. Antibody blocking studies reveal that neurotoxicity is almost entirely attributable to complement. Remarkably, loss of a single allele of Cebpb prevented the pro-inflammatory phenotype. COP1-deficient microglia markedly accelerated tau-mediated neurodegeneration in a mouse model where elevated ApoE plays a deleterious role. Collectively, these results identify c/EBPß as a potential therapeutic target for inflammation-driven neurodegeneration.

2020-08-14 | GSE145454 | GEO

EGFR is a target of the tumor suppressor E3-ligase FBXW7

Project description:FBXW7 is and E3 ubiquitin ligase and is highly mutated in colorectal cancer. We used human colon organoids with engineered FBXW7 hotspot mutations to investigate novel targets of E3 ligase activity with a combined transcriptomic and proteomic approach uncovering the EGFR-MAPK pathway as highly regulated by the E3 ligase activity.

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Transcriptomic profiling of Cop1-deficient embryos

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In vivo CRISPR screens identify the E3 ligase Cop1 as a modulator of macrophage infiltration and cancer immunotherapy target.

Project description:Despite remarkable clinical efficacy of immune checkpoint blockade (ICB) in cancer treatment, ICB benefits for triple-negative breast cancer (TNBC) remain limited. Through pooled in vivo CRISPR knockout (KO) screens in syngeneic TNBC mouse models, we found that deletion of the E3 ubiquitin ligase Cop1 in cancer cells decreases secretion of macrophage-associated chemokines, reduces tumor macrophage infiltration, enhances anti-tumor immunity, and strengthens ICB response. Transcriptomics, epigenomics, and proteomics analyses revealed that Cop1 functions through proteasomal degradation of the C/ebpδ protein. The Cop1 substrate Trib2 functions as a scaffold linking Cop1 and C/ebpδ, which leads to polyubiquitination of C/ebpδ. In addition, deletion of the E3 ubiquitin ligase Cop1 in cancer cells stabilizes C/ebpδ to suppress expression of macrophage chemoattractant genes. Our integrated approach implicates Cop1 as a target for improving cancer immunotherapy efficacy in TNBC by regulating chemokine secretion and macrophage infiltration in the tumor microenvironment.

| S-EPMC9136996 | biostudies-literature

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