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Silencing of the Stat1-bcl2 axis accelerates efficient apoptosis of immature T lymphocytes with DNA damage in zebrafish mcm5 mutants

ABSTRACT: Silencing of the Stat1-bcl2 axis accelerates efficient apoptosis of immature T lymphocytes with DNA damage in zebrafish mcm5 mutants

PROVIDER: PRJNA989221 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25076624_1.fastq.gz	Fastqsanger.gz
	SRR25076624_2.fastq.gz	Fastqsanger.gz
	SRR25076625_1.fastq.gz	Fastqsanger.gz
	SRR25076625_2.fastq.gz	Fastqsanger.gz
	SRR25076626_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Silencing of the Stat1-bcl2 axis accelerates efficient apoptosis of immature T lymphocytes with DNA damage in zebrafish mcm5 mutants

Project description:In this research, we found mcm5 mutation lead to T cell deficiency and apoptosis in zebrafish. To reveal the molecular mechanism of mcm5 mutation in regulating T cell maturation, we performed RNA-Seq to discover the signal pathways regulated by mcm5.

2023-06-30 | GSE236184 | GEO

Mcm5 mutation leads to silencing of Stat1-bcl2 which accelerating apoptosis of immature T lymphocytes with DNA damage.

Project description:Mutation in genes involved in DNA replication continuously disrupt DNA replication and give rise to genomic instability, a critical driver of oncogenesis. To prevent leukemia, immature T lymphocytes with genomic instability often undergo rapid cell death during development. However, the mechanism by which immature T lymphocytes undergo rapid cell death upon genomic instability has been enigmatic. Here we show that zebrafish mcm5 mutation leads to DNA damage in immature T lymphocytes and the immature T cells sensitively undergo rapid cell death. Detailed analyses demonstrated that the immature T lymphocytes undergo rapid apoptosis via upregulation of tp53 and downregulation of bcl2 transcription in mcm5 mutants. Mechanistically, Mcm5 directly binds to Stat1a and facilitates its phosphorylation to enhance bcl2a expression under the conditions of DNA replication stress. However, in mcm5 mutants, the absence of the Mcm5-Stat1 complex decreases Stat1 phosphorylation and subsequent bcl2a transcription, accelerating apoptosis of immature T lymphocytes with genomic instability. Furthermore, our study shows that the role of Mcm5 in T-cell development is conserved in mice. In conclusion, our work identifies a role of Mcm5 in regulating T cell development via Stat1-Bcl2 cascade besides its role in DNA replication, providing a kind of mechanism by which immature T cells with gene mutation-induced DNA damage are rapidly cleared during T lymphocyte development.

| S-EPMC11811017 | biostudies-literature

Gene expression profile of the human T-ALL cell line JURKAT after TYK2 and STAT1 knockdown

Project description:Targeted molecular therapy has yielded remarkable outcomes in certain cancers, but specific therapeutic targets remain elusive for many others. As a result of two independent RNA interference (RNAi) screens, we identified pathway dependence on a member of the JAK tyrosine kinase family, TYK2, and its downstream effector STAT1 in T-cell acute lymphoblastic leukemia (T-ALL). Gene knockdown experiments consistently demonstrated TYK2 dependence in both T-ALL primary specimens and cell lines, and a small-molecule inhibitor of JAK kinase activity induced T-ALL cell death. Activation of this TYK2-STAT1 pathway in T-ALL cell lines occurs by gain-of-function TYK2 mutations or activation of IL-10 receptor signaling, and this pathway mediates T-ALL cell survival through upregulation of the anti-apoptotic protein BCL2. These findings indicate that in many T-ALL cases, the leukemic cells are dependent upon the TYK2-STAT1-BCL2 pathway for continued survival, supporting the development of molecular therapies targeting TYK2 and other components of this pathway. Human T-ALL cell line JURKAT cells were transduced with TYK2 (TYK2#2 or #3), STAT1 (STAT1#2 or #3) or control shRNAs (GFP and Luc). Experiment was done in biological duplicate ("dup1" and "dup2") . A total of 12 RNA samples (4 control, 4 TYK2 knockdown and 4 STAT1 knockdown) were used for microarray gene expression analysis.

2013-03-18 | E-GEOD-44652 | biostudies-arrayexpress

Gene expression profile of the human T-ALL cell line JURKAT after TYK2 and STAT1 knockdown

2013-03-18 | GSE44652 | GEO

Pancreatic Gene Expression from Wild-Type, Stat1-Transgenic, and Stat1-CC-Transgenic Mice

Project description:Pancreatic Gene Expression from Wild-Type, Stat1-Transgenic, and Stat1-CC-Transgenic Mice. This data was part of the set of data utilized to identify PARP9/DTX3L as a novel antiviral gene. Keywords: transgene state analysis RNA was extracted from the pancreas of 3 mice per genotype (wild-type, Stat1-Transgenic, Stat1-CC-Transgenic). Comparisons were made between Stat1-Transgenic and Stat1-CC-Transgenic mice.

2015-09-01 | E-GEOD-61414 | biostudies-arrayexpress

Guanylate binding protein 5 accelerates gastric cancer progression via a JAK1-STAT1/GBP5/CXCL8 positive feedback loop

Project description:Guanylate binding protein 5 accelerates gastric cancer progression via a JAK1-STAT1/GBP5/CXCL8 positive feedback loop

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Musashi 2 regulates normal hematopoiesis and accelerates leukemogenesis

Project description:This SuperSeries is composed of the following subset Series: GSE16432: MSI2 regulates hematopoiesis and accelerates leukemogenesis GSE22773: Musashi 2 regulates normal hematopoiesis and accelerates leukemogenesis (LK and MS12-inducible) GSE22774: Musashi 2 regulates normal hematopoiesis and accelerates leukemogenesis (LSK and LK) GSE22775: Musashi 2 regulates normal hematopoiesis and accelerates leukemogenesis (Leukemia cell lines) Refer to individual Series

2010-07-21 | E-GEOD-22778 | biostudies-arrayexpress

A feedforward loop between STAT1 and YAP1 stimulates lipid biosynthesis, accelerates tumor growth, and promotes chemotherapy resistance in mutant KRAS colorectal cancer.

Project description:In tumorous conditions, the transcription factor STAT1, traditionally recognized for its anti-tumor role in immunology, exhibits pro-survival characteristics, though the underlying mechanisms remain unclear. Investigating STAT1's function in isogenic colorectal tumor cells with wild-type or mutant KRAS, we found that STAT1 specifically promotes the survival and proliferation of cells with mutant KRAS. Through gene expression profiling, we discovered a previously unknown role of STAT1 in upregulating sterol and lipid biosynthetic genes specifically in mutant KRAS cells. This effect is driven by STAT1’s phosphorylation at serine 727 and its cooperation with STAT3 and STAT5 for the transcriptional upregulation of sterol regulatory element-binding proteins (SREBP) 1 and 2, which boost de novo sterol and lipid biosynthesis. In mutant KRAS cells, STAT1 amplifies the mevalonate pathway, maintaining its serine 727 phosphorylation through the upregulation of RHO GTPase signaling and establishing a positive feedback loop through the transcription factors YAP1 and TEAD4, further driving lipid biosynthesis and tumor growth. Through xenograft tumor assays in mice, we discovered that the STAT1-YAP1 axis plays a role in mutant KRAS tumor cells' resistance to mevalonate pathway inhibitors, which can be overcome by pharmacologically targeting the YAP1-TEAD interaction. Additionally, the STAT1-YAP1 arm is essential for the intrinsic resistance to EGFR-targeting therapy in the mutant KRAS colon cancer cells. These findings indicate that the STAT1-YAP1 pathway plays a significant role in therapy resistance and presents a potential therapeutic target in mutant KRAS colorectal cancer. We used microarrays to detail the global programme of gene expression underlying genes commonly regulated by STAT1 and YAP1 in HCT116 cells.

2024-10-03 | GSE278710 | GEO

Impact of androgen stimulation on BCL2 Overexpressed LNCaP cells

Project description:In analyzing transcriptomic data from a clinical trial of neoadjuvant-intensive Androgen Deprivation Therapy, we observed increased mRNA expression of the hallmark antiapoptotic gene BCL2 in the prostate tumors of treated patients versus those of untreated patients. We showed that BCL2 overexpressed LNCaP cells exhibited resistance to enzalutamide, indicating that BCL2-overexpression leads to castration resistance and cellular plasticity.We performed RNA sequencing on BCL2 overexpressed LNCaP cells tretaed with R1881 to determine BCL2 regulated AR signaling and overed that BCL2 overexpression may alter AR-pathway.

2025-05-15 | GSE273737 | GEO

Combinatorial targeting of MYC/BCL2 double-hit lymphoma with mitochondrial complex I and BCL2 inhibitors

Project description:Activation of the MYC oncogene is common in B-cell lymphomas, and frequently associated with compensatory events that dampen Myc-induced apoptosis, such as over-expression of anti-apoptotic Bcl2-family proteins. For example, concurrent translocations of MYC and BCL2 in a subset of Diffuse large B-cell lymphoma (DLBCL) lead to the high-grade “double-hit” lymphoma subtype (DHL), characterized by dismal prognosis in the face of current front-line regimens, thus calling for the pursuit of tailored therapeutic strategies. Here, we show that Myc and Bcl2 modulate the sensitivity of B-cells to IACS-010759, a selective inhibitor of mitochondrial respiratory complex I. Myc activation in non-transformed lymphoid precursors suppressed endogenous Bcl2 and sensitized the cells to IACS-010759-induced apoptosis. Treatment with the Bcl2 inhibitor venetoclax also sensitized to IACS-010759, while overexpression of Bcl-2 was protective. IACS-010759 engaged an ATF4-driven Integrated Stress Response (ISR) with dual anti- and pro-apoptotic effects, the latter mediated by the CHOP transcription factor, which contributed to selective killing of Myc-overexpressing cells. In line with the above data, IACS-010759 and venetoclax synergized in killing human DHL cells, and showed strong combinatorial effects in a pre-clinical setting. In a Bcl2-negative Burkitt’s lymphoma cell line, instead, IACS-010759 synergized with the Mcl-1 inhibitor S63845. Altogether, our data point to the combination of IACS-010759 with distinct Bcl2-family inhibitors for therapeutic reactivation of the intrinsic apoptotic pathway in Myc-associated B-cell lymphomas

2022-03-01 | GSE149073 | GEO

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