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The SRC-family kinase LYN acts as a tumour suppressor gene in an in vivo BRCA1 loss-of-function-associated mammary tumourigenesis model

ABSTRACT: The SRC-family kinase LYN acts as a tumour suppressor gene in an in vivo BRCA1 loss-of-function-associated mammary tumourigenesis model

PROVIDER: PRJNA917599 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR22956700_1.fastq.gz	Fastqsanger.gz
	SRR22956700_2.fastq.gz	Fastqsanger.gz
	SRR22956701_1.fastq.gz	Fastqsanger.gz
	SRR22956701_2.fastq.gz	Fastqsanger.gz
	SRR22956702_1.fastq.gz	Fastqsanger.gz

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The SRC-family kinase LYN acts as a tumour suppressor gene in an in vivo BRCA1 loss-of-function-associated mammary tumourigenesis model

Project description:To examine the interaction between LYN kinase and BRCA1 loss-of-function in an in vivo mouse mammary tumour model, we have used conditional knockout Brca1 and Lyn alleles targeted to the mammary epithelium, on a p53 heterozygote background. Comparison of tumour cohorts demonstrated that homozygous conditional Lyn cohorts developed tumours significantly faster than the other genotypes. Transcriptomic analysis to identify and compare tumours with the highest and lowest Lyn levels from across the cohorts showed that ‘Lyn high’ tumours had a significantly slower doubling time and were enriched in inflammatory pathways and canonical NfkB signalling. ‘Lyn low’ tumours had a faster doubling time and were enriched in PI3K, WNT and NOTCH pathways. Therefore, these results suggest that, in this model at least, LYN acts as a tumour suppressor in the context of Brca1 loss.

2023-01-23 | GSE222075 | GEO

Tyrosine Phosphorylation of NLRP3 by Src Family Protein Tyrosine Kinase Lyn Suppresses NLRP3 Inflammasome Activation

Project description:The NLRP3 inflammasome is a multi-protein complex that triggers the activation of the inflammatory protein caspase-1 and the maturation of the cytokine IL-1 in response to microbes and other danger signals in host cells. Here, we sought a deeper understanding of how the NLRP3 inflammasome is regulated. We found that inflammasome activation induced the Src family kinase Lyn to phosphorylate NLRP3 at Tyr918, and that this phosphorylation of NLRP3 correlated with a subsequent increase in its ubiquitination, which facilitated its proteasome-mediated degradation. NLRP3 tyrosine phosphorylation and ubiquitination was abrogated in Lyn-deficient macrophages, which produced increased amounts of IL-1. Furthermore, mice lacking Lyn were highly susceptible to LPS-induced septic shock in an NLRP3-dependent manner. Our data demonstrate that Lyn-mediated tyrosine phosphorylation of NLRP3 is a prerequisite for its ubiquitination, thus dampening NLRP3 inflammasome activity.

2022-05-19 | PXD028582 | Pride

Src heterodimerically activates Lyn or Fyn to serve as targets for esophageal squamous cell carcinoma (ESCC) diagnosis and treatment

Project description:we combined phosphoproteomics and several cellular and molecular biologic strategies to identify that Src specifically interacted with the members of Src-family kinases (SFKs), such as Fyn or Lyn to form heterodimers, and subsequently phosphorylate the tyrosine sites in SH2 and kinase domains, which critically contributed to the ESCC malignancy.

2022-03-15 | PXD032306 |

Gene expression profiling in wild-type, Irf5-KO, Lyn-KO and Lyn/Irf5-DKO BMDCs unstimulated or stimulated with CpG-B ODN

Project description:To characterize the relationship between IRF5 and Lyn in innate immune responses at a genome-wide scale, we performed gene expression microarray analysis for wild-type (WT), Irf5-KO, Lyn-KO and Lyn/Irf5-DKO bone marrow-derived dendritic cells (BMDCs) with or without 6 h-stimulation with 150 nM CpG-B ODN. We extracted the transcripts that were upregulated by CpG-B ODN in WT BMDCs, further upregulated in Lyn-KO BMDCs and then downregulated in Lyn/Irf5-DKO BMDCs (fold change ≥ 2, false discovery rate < 0.05). When these 79 transcripts were sorted by their expression levels in Lyn-KO BMDCs, most of the top 20 genes (13 out of 20) were those encoding type I interferons (IFNs), indicating that Lyn particularly suppresses IRF5 induction of type I IFNs.

2016-07-25 | GSE63014 | GEO

Gene expression profiling in wild-type, Irf5-KO, Lyn-KO and Lyn/Irf5-DKO BMDCs unstimulated or stimulated with CpG-B ODN

Project description:To characterize the relationship between IRF5 and Lyn in innate immune responses at a genome-wide scale, we performed gene expression microarray analysis for wild-type (WT), Irf5-KO, Lyn-KO and Lyn/Irf5-DKO bone marrow-derived dendritic cells (BMDCs) with or without 6 h-stimulation with 150 nM CpG-B ODN. We extracted the transcripts that were upregulated by CpG-B ODN in WT BMDCs, further upregulated in Lyn-KO BMDCs and then downregulated in Lyn/Irf5-DKO BMDCs (fold change â?¥ 2, false discovery rate < 0.05). When these 79 transcripts were sorted by their expression levels in Lyn-KO BMDCs, most of the top 20 genes (13 out of 20) were those encoding type I interferons (IFNs), indicating that Lyn particularly suppresses IRF5 induction of type I IFNs. BMDCs from WT, Irf5-KO, Lyn-KO and Lyn/Irf5-DKO mice in a C57BL/6 background were unstimulated or stimulated with CpG-B ODN. Biological triplicate for each genotype were analyzed (24 samples in total).

2016-07-25 | E-GEOD-63014 | biostudies-arrayexpress

Transcriptome of LYN deficient HS-5 stroma cells

Project description:LYN kinase is a tyrosine kinase, that regulates cellular homeostasis in a context-specific manner. Our group could show, that its expression in the leukemic microenvironment of chronic lymphocytic leukemia contributes to disease progression (Nguyen PH et al.; Cancer Cell; 2016). To analyze the effect of LYN kinase on the leukemia supportive phenotype of the bone marrow stromal cell line HS-5, we generated single cell clones of LYN deficient stroma cells. These cells were analyzed in a Multi-Omic approach, including microarray based analysis of the transcriptome.

2023-01-01 | E-MTAB-10980 | biostudies-arrayexpress

RNA-Seq analysis of LYN deficient stromal cells sorted from murine spleens

Project description:LYN kinase is a tyrosine kinase, that regulates cellular homeostasis in a context-specific manner. Our group could show, that its expression in the leukemic microenvironment of chronic lymphocytic leukemia contributes to disease progression (Nguyen PH et al.; Cancer Cell; 2016). We analyzed the effect of LYN deficiency on murine splenic stromal cells by FACS-sorting stroma cells from Lyn(wt/wt) and Lyn(-/-) spleen (7AAD-Cd45-Cd71-Cd31-Cd26+Cd54+).

2023-02-10 | E-MTAB-12630 | biostudies-arrayexpress

Leukemic cells expressing NCOR1-LYN are sensitive to dasatinib in vivo in a patient-derived xenograft mouse model

Project description:Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a distinct subtype of B-ALL with a poor prognosis. Rearrangement of LYN is a recurrent genetic abnormality in Ph-like ALL, but functional analysis of LYN-related fusion genes identified in ALL has not been reported. In this study, we performed functional analysis of the NCOR1-LYN fusion gene identified in a pediatric Ph-like ALL patient to establish its potential for molecular targeted therapy. Retroviral transduction of interleukin (IL)-3-dependent Ba/F3 cells with NCOR1-LYN enabled IL-3-independent proliferation, with constitutive phosphorylation of the tyrosine residues of the LYN kinase domain in the fusion protein. Replacing tyrosine residues with phenylalanine in the LYN kinase domain abolished IL-3 independence. Tyrosine kinase inhibitor dasatinib killed Ba/F3 cells expressing NCOR1-LYN in vitro accompanied by dephosphorylation of the tyrosine residues of the LYN kinase domain in the fusion protein. In a patient-derived xenograft (PDX) mouse model, generated using leukemic cells from the NCOR1-LYN positive Ph-like ALL patient, dasatinib controlled the growth of leukemic cells in vivo and significantly extended the survival time of the PDX mice (p=0.03). Our data demonstrate that, like other kinase fusions identified in Ph-like ALL, the NCOR1-LYN rearrangement has proliferative activity, and that tyrosine phosphorylation of the LYN kinase domain is critical for IL-3 independent growth. Furthermore, in a preclinical model we demonstrate the efficacy in vivo of dasatinib as therapy for Ph-like ALL with a LYN rearrangement.

2020-03-21 | GSE147281 | GEO

ATAC-Seq analysis of LYN deficient HS-5 stroma cells

2024-01-01 | E-MTAB-12531 | biostudies-arrayexpress

RNAseq of Brca1-deficient mouse mammary tumors

Project description:Brca1 mutation predisposes women to early onset of breast and ovarian cancers.Through its diverse functions in DNA damage repair, cell cycle control, transcription regulation, ubiquitination and so on, BRCA1 acts as a very significant tumor suppressor and genomic safeguard. Brca1 deficiency induces severe cellular stress, when occurring in the mammary glands, it impairs the regular developmental process and eventually causes tumorigenesis due to accumulation of genome instability and other mechanisms. The Brca1-defiencient mouse mammary tumor were characterized with great tumoral heterogeneity, which is in line with the human breast cancers carrying BRCA1 mutations. Here we studied the molecular complexicity of Brca1-deficient mouse mammary tumors vie RNA sequencing.

2021-11-17 | GSE148565 | GEO

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