C-Myc uses Cul4b to preserve genome stability and promote CD8+ T cell-mediated antiviral immune responses
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA951219 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24039373_1.fastq.gz | Fastqsanger.gz | |||
| SRR24039373_2.fastq.gz | Fastqsanger.gz | |||
| SRR24039374_1.fastq.gz | Fastqsanger.gz | |||
| SRR24039374_2.fastq.gz | Fastqsanger.gz | |||
| SRR24039375_1.fastq.gz | Fastqsanger.gz |
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Project description:During infection, virus-specific CD8+ T cells undergo rapid bursts of proliferation and differentiate into effector cells that kill virus infected cells and reduce viral load. This rapid clonal expansion can put T cells at significant risk for replication-induced DNA damage. We found that c-Myc utilizes the E3 ubiquitin ligase, Cul4b, to inextricably link CD8+ T cell expansion to DNA damage response pathways. Following activation, c-Myc increased levels of Cul4b and other members of the CRL4 complex. Despite having abundant c-Myc expression, Cul4b-deficient CD8+ T cells were unable to expand and clear virus. Cul4b-deficient CD8+ T cells accrued DNA damage and succumbed to proliferative catastrophe early after antigen encounter. Mechanistically, Cul4b ablation induced a protracted accumulation of p21 and Cyclin E2 resulting in replication stress. Our data show that, to support cell proliferation, c-Myc must employ Cul4b to maintain genome stability, thereby directly coupling these two interdependent pathways. These data clarify how CD8+ T cells use c-Myc and Cul4b to sustain their potential for extraordinary population expansion, longevity and antiviral responses.
2023-08-30 | GSE228695 | GEO
Project description:During infection, virus-specific CD8+ T cells undergo rapid bursts of proliferation and differentiate into effector cells that kill virus infected cells and reduce viral load. This rapid clonal expansion can put T cells at significant risk for replication-induced DNA damage. We found that c-Myc utilizes the E3 ubiquitin ligase, Cul4b, to inextricably link CD8+ T cell expansion to DNA damage response pathways. Following activation, c-Myc increased levels of Cul4b and other members of the CRL4 complex. Despite having abundant c-Myc expression, Cul4b-deficient CD8+ T cells were unable to expand and clear virus. Cul4b-deficient CD8+ T cells accrued DNA damage and succumbed to proliferative catastrophe early after antigen encounter. Mechanistically, Cul4b ablation induced a protracted accumulation of p21 and Cyclin E2 resulting in replication stress. Our data show that, to support cell proliferation, c-Myc must employ Cul4b to maintain genome stability, thereby directly coupling these two interdependent pathways. These data clarify how CD8+ T cells use c-Myc and Cul4b to sustain their potential for extraordinary population expansion, longevity and antiviral responses.
2023-08-29 | PXD041220 | Pride
Project description:During infection, virus-specific CD8+ T cells undergo rapid bursts of proliferation and differentiate into effector cells that kill virus-infected cells and reduce viral load. This rapid clonal expansion can put T cells at significant risk for replication-induced DNA damage. Here, we find that c-Myc links CD8+ T cell expansion to DNA damage response pathways though the E3 ubiquitin ligase, Cullin 4b (Cul4b). Following activation, c-Myc increases the levels of Cul4b and other members of the Cullin RING Ligase 4 (CRL4) complex. Despite expressing c-Myc at high levels, Cul4b-deficient CD8+ T cells do not expand and clear the Armstrong strain of lymphocytic choriomeningitis virus (LCMV) in vivo. Cul4b-deficient CD8+ T cells accrue DNA damage and succumb to proliferative catastrophe early after antigen encounter. Mechanistically, Cul4b knockout induces an accumulation of p21 and Cyclin E2, resulting in replication stress. Our data show that c-Myc supports cell proliferation by maintaining genome stability via Cul4b, thereby directly coupling these two interdependent pathways. These data clarify how CD8+ T cells use c-Myc and Cul4b to sustain their potential for extraordinary population expansion, longevity and antiviral responses.
| S-EPMC10625626 | biostudies-literature
Project description:It has been reported that PHF1, CUL4B and PRMT5 all play important roles in epigenetic regulation. We reported that PHF1, CRL4B and PRMT5 may act as a complex in transcriptional regulation and have a vital effect in breast cancer progression. So we performed ChIP-on-chip assays to find unique promoters co-targeted by PHF1, CUL4B and PRMT5. PHF1, CUL4B and PRMT5 have a predominant cooperation, at least in MDA-MB-231 cells. comparison of PHF1, CUL4B and PRMT5 target genes
2016-07-07 | E-GEOD-84071 | biostudies-arrayexpress
Project description:We examined a global miRNA expression in CUL4B-depleted LNCaP cells to identify miRNA(s) regulated by CUL4B.
2019-04-13 | GSE129737 | GEO
Project description:Cullin 4B (CUL4B) is a scaffold protein of the CUL4B-Ring E3 ligase (CRL4B) complex. Here, we found that CRL4B interacted with transcriptional corepressor complexes. Our results supporting CUL4B as a potential target of cancer therapy.
2021-03-25 | GSE124611 | GEO
Project description:Cullin 4B (CUL4B), a scaffold protein that assembles CRL4B ubiquitin ligase complexes, has been reported to be overexpressed in several types of solid tumors and contributes to epigenetic silencing of tumor suppressor. However, its clinical significance and the molecular mechanisms underlying its regulation in gastric cancer (GC) remain largely unknown. Here, we showed that CUL4B was elevated in GC tissues and its overexpression was positively correlated with poor prognosis and lymph node metastasis. CUL4B knockdown in GC cells decreased proliferation, mesenchymal transition and invasion in vitro, as well as tumor growth and metastasis in nude mice, and CUL4B overexpression induced the opposite results. Further studies showed that miR-101 could inhibit CUL4B expression by directly targeting its 3’-UTR and they were inversely correlated in clinical GC specimens. Notably, a positive relationship between CUL4B and HER2 was found in GC clinical specimens, GC cells and GC xenograft tumors. Through bioinformatics analysis of miRNA-seq data and target prediction, we nominated miR-125a as a direct target of CUL4B. ChIP assays demonstrated that CUL4B directly repressed miR-125a expression by physically binding to its promoter. In addition, we confirmed miR-125a is the target of HER2. Consequently, we demonstrated that CUL4B can up-regulate HER2 expression through repressing miR-125a. Most importantly, silencing of HER2 by Herceptin or siRNA partially reversed CUL4B-induced epithelial-to-mesenchymal transition (EMT), cell invasion and metastasis in vitro and in vivo. These findings define a CUL4B-miR-125a-HER2 regulatory mechanism shed light on CUL4B oncogenic mechanisms and reveals promising therapeutic targets for progressive GC. CUL4B proteins are frequently upregulated in human cancer, yet little is known about the underlying molecular mechanisms of CUL4B induced gastric cancer(GC) carcigenesis.Here, we uncover the critical role of CUL4B in gastric cancer growth and metastasis through the regulation of HER2 expression.CUL4B contributes to GC invasion and metastasis by transcriptional repression of HER2 targeting miR-125a, which provide a new insight into how CUL4B regulates GC progression and metastasis.
2017-11-25 | GSE90501 | GEO
Project description:Approximately 30% of cases are resistant to TAM, which has become a major obstacle for breast cancer therapy.In this study, we demonstrated that CUL4B promotes TAM resistance in breast cancer cells through miR-32-5p/ER-α36 axis. CUL4B is overexpressed in TAM-resistant breast cancer cells and positively correlates with the levels of ER-α36 protein in human breast cancer specimens. Mechanistically, CUL4B positively regulates ER-α36 expression by epigenetically repressing the transcription of miR-32-5p. These findings provide not only a mechanistic insight into the role of CUL4B in regulating TAM sensitivity but also a potential target for the therapy of breast cancer.
2022-09-08 | GSE158651 | GEO
Project description:Cullin 4B (CUL4B) is a scaffold protein of E3 ubiquitin ligase complex and has been found frequently overexpressed in various types of cancer. By repressing tumor suppressors, CUL4B is indicated as pro-oncogenic gene in oncogenesis. Reversely, recent studies reveal that deletion of CUL4B in hematopoietic system exerts tumor suppressive effect in tumor bearing hosts. However, the role of CUL4B in tumor initiation remains unknown. Here we report that CUL4B deficiency in the intestinal epithelium accelerates ApcMin/+ tumor formation. CUL4B in cancer cells restricts the accumulation of tumor-infiltrating CD11b+Gr-1+ MDSCs to prohibit the adenoma permissive microenvironment and thus increases the number of antitumor CD8+ T cells. Addition of MDSCs to ex vivo cultured ApcMin/+; Cul4bΔIEC tumor organoids rescues their phenotypic alteration in stemness, suggesting a reciprocally strengthened immunosuppressive effect between CUL4B deficient tumor cells and MDSCs. Mechanistically, inhibiting CUL4B epigenetically activates the expression of secreted chemokines and proteins including G-CSF to enroll MDSCs. Our findings suggest that epithelial deletion of CUL4B creates a tumor-prone microenvironment during ApcMin/+ tumor formation and provide a potential strategy to overcome colon cancer initiation and progress in the Wnt-disturbed context.
2024-11-20 | GSE189382 | GEO
Project description:A total of 619 unique promoters were found to be co-targeted by CUL4B and EZH2, among which only 53 were overlapped with the 891 targets of BMI EZH2/PRC2 and CUL4B/CRL4B have a predominant cooperation, at least in KYSE410 cells.
2012-10-17 | GSE41639 | GEO