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Gene expression patterns induced by 5-Fluorouracil in breast cancer cell lines

ABSTRACT: We have compared the changes in cell cycle and cell death parameters induced by 2 different concentrations of 5-FU (IC50 and IC80) in the breast adenocarcinoma cell line MCF7. G1/S cell cycle arrest was associated with both concentrations, whereas cell death was mainly induced after IC80 5-FU. These changes were correlated with gene expression assessed by cDNA microarray analysis. Main findings included an overexpression of p53 target genes involved in cell cycle and apoptosis (CDKN1A/p21, TP53INP, TNFRSF6/FAS and BBC3/PUMA), and significant repression of Myc. High dose 5-FU also induced a higher regulation of the mitochondrial death genes APAF1, BAK1 and BCL2, and induction of genes of the ID family. Keywords: Dose Response

ORGANISM(S): Homo sapiens

PROVIDER: GSE2584 | GEO | 2006/04/07

SECONDARY ACCESSION(S): PRJNA91993

REPOSITORIES: GEO

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Gene expression patterns induced by 5-Fluorouracil in breast cancer cell lines

Project description:We have compared the changes in cell cycle and cell death parameters induced by 2 different concentrations of 5-FU (IC50 and IC80) in the breast adenocarcinoma cell line MCF7. G1/S cell cycle arrest was associated with both concentrations, whereas cell death was mainly induced after IC80 5-FU. These changes were correlated with gene expression assessed by cDNA microarray analysis. Main findings included an overexpression of p53 target genes involved in cell cycle and apoptosis (CDKN1A/p21, TP53INP, TNFRSF6/FAS and BBC3/PUMA), and significant repression of Myc. High dose 5-FU also induced a higher regulation of the mitochondrial death genes APAF1, BAK1 and BCL2, and induction of genes of the ID family. Time and dose-dependent changes in gene expression, induced by 5-Fluorouracil, in breast carcinoma cell lines MCF7, and MDA-MB-435.

2010-07-01 | E-GEOD-2584 | biostudies-arrayexpress

Repression of p53-target gene Bbc3/puma by MYSM1 is essential for the survival of hematopoietic multipotent progenitors and contributes to stem cell maintenance

Project description:MYSM1 is a transcriptional regulator essential for HSC function and hematopoiesis. We established that p53 activation is a common mechanism mediating HSC dysfunction, MPP depletion, and lymphopenia in Mysm1-deficiency, however, the specific p53-induced effectors that trigger dysfunction in Mysm1-deficient HSPCs remain unknown. Here, we performed RNA-Seq of Lin-cKit+Sca1+CD150+ and CD150- HSPCs from Mysm1-/-Puma-/-, Mysm1-/-Puma+/-, Puma-/-, and wild-type mice; (Mysm1-/-Puma+/- phenocopies Mysm1-/-). We showed that Bbc3/PUMA is the primary non-redundant mediator of MPP depletion in Mysm1-deficiency and contributes to HSC dysfunction, whereas depletion of lymphoid-lineage cells involves PUMA-independent p53 activities. We also identified a broad downregulation of genes encoding protein components of the ribosome (RP-genes) and other regulators of translation in Mysm1-deficiency, and the downregulation persisted in Mysm1-/-Puma-/-.

2020-07-22 | GSE150665 | GEO

Interactome of Arabidopsis BIR3 protein

Project description:Arabidopsis BAK1/SERK3, a co-receptor of leucine-rich repeat pattern recognition receptors (PRR), mediates pattern-triggered immunity (PTI). Genetic inactivation of BAK1 or BAK1-interacting receptors (BIR) causes cell death. We foundthat the TIR-NBS-LRR protein CONSTITUTIVE SHADE-AVOIDANCE 1 (CSA1) physically interacts with BIR3, but not with BAK1 and mediates ETI-type cell death in the absence of BAK1 and BIR3.

2022-11-29 | PXD036942 | Pride

Phase II study of 5-FU dose-adjusted mFOLFOX7 plus Bevacizumab for patients with metastatic colorectal cancer(AJUST study)

Project description:Interventions: L-OHP 85mg/m^2 day1 Infusional 5-FU 2400mg/m^2 46hours l-LV 200mg/m^2 day1 Bmab 5mg/kg day1 every 2 weeks At first cycle, 5-FU concentrations are monitored. After second cycle, 5-FU are administered by the adjusted dose to mFOLFOX7+Bmab. Primary outcome(s): Response Rate Study Design: Single arm Non-randomized

| 2622613 | ecrin-mdr-crc

Sca1+ macrophages activate hematopoietic stem/progenitor cells upon bone marrow stress. [scRNA-Seq]

Project description:Although hematopoietic stem and progenitor cells (HSPCs) become activated in the cell-cycle status after chemotherapy to supply hematopoietic loss, the detailed mechanisms of activation remain unknown. Here we show that Sca1+ macrophages play a key role for bone marrow (BM) recovery through granulocyte-macrophage colony-stimulating factor (GM-CSF) secretion. By analyzing gene expression profiles of HSPCs lodged in 5-fluolouracil (5-FU)-treated mice, we found GM-CSF as a key proliferative signal. Sca1+ macrophages in BM after 5-FU treatment expressed high levels of GM-CSF. GM-CSF-knockout mice treated with 5-FU were lethal because of severe BM suppression. Up-regulation of Csf2 in Sca1+ macrophages by 5-FU was suppressed in MyD88-knockout mice, suggesting that TLR signaling via damage-associated molecular patterns caused by cell death is critical for up-regulation of Csf2. In 5-FU treated BM, majority of Sca1+ macrophages and transplanted HSPCs locate perivascular areas. These findings together indicate that Sca1+ macrophages induce HSPCs to proliferate through GM-CSF signaling in the stressed BM environments.

2021-01-20 | GSE120112 | GEO

Sca1+ macrophages activate hematopoietic stem/progenitor cells upon bone marrow stress. [RNA-Seq]

2021-01-20 | GSE120111 | GEO

Transcription profiling of non-small cell lung carcinoma cell line H1975 treated with cisplatin or BMS-69014 a novel panHER/VEGFR inhibitor

Project description:Non-small cell lung cancer (NSCLC) with activating mutations in the epidermal growth factor receptor (EGFR) responds to EGFR tyrosine kinase inhibitors such as erlotinib. However, secondary somatic EGFR mutations (e.g. T790M) confer resistance to erlotinib. BMS-690514, a novel panHER/VEGFR inhibitor described here, exerted antiproliferative and pro-apoptotic effects on NSCLC cell lines, with prominent efficacy on H1975 cells expressing the T790M mutation. In this model, BMS-690514 induced a G1 cell cycle arrest, as well as ultrastructural hallmarks of apoptosis, mitochondrial release of cytochrome c, and activation of caspases involved in the intrinsic (e.g. caspase -2, -3, -7 and -9), but not in the extrinsic (e.g. caspase-8) pathway. Caspase inhibition conferred partial protection against BMS-690514 cytotoxicity, pointing to the involvement of both caspase-dependent and -independent effector mechanisms. Transcriptome analyses revealed the upregulation of pro-apoptotic (e.g. Bim, Puma) and cell cycle inhibitory (e.g. p27Kip1, p57Kip2) factors, as well as the downregulation of anti-apoptotic (e.g. Mcl1), heat shock (e.g. HSP40, HSP70, HSP90) and cell cycle promoting (e.g. cyclins B1, D1 and D3, CDK1, MCM family proteins, PCNA) proteins. BMS-690514-induced death of H1975 cells was modified in a unique fashion by a panel of siRNAs targeting apoptosis modulators. Downregulation of components of the NF-kappaB survival pathway (e.g. p65, Nemo/IKK, TAB2) sensitized cells to BMS-690514, whereas knockdown of pro-apoptotic factors (e.g. Puma, Bax, Bak, caspase-2, etc) and DNA damage-related proteins (e.g. ERCC1, hTERT) exerted cytoprotective effects. BMS-690514 is a new pan-HER/VEGFR inhibitor that may become an alternative to erlotinib for the treatment of NSCLC.

2007-07-24 | E-TABM-239 | biostudies-arrayexpress

New insights into the molecular mechanisms of 1,3-dinitrobenzene-induced testicular toxicity

Project description:Several studies have shown that 1,3-dinitrobenzene (DNB) causes injury to Sertoli cells and induces apoptosis in the surrounding germinal cells in male laboratory rats ; however, the mechanisms by which DNB functions are not well understood. In this context, we have conducted studies using standard parameters and molecular tools to better understand the pathogenesis of the testicular effects produced by DNB, as well as its mode of action. Wistar rats were orally exposed to 0.1-8 mg DNB/kg/day for 4 days. Testosterone concentrations were not affected at any dose level, but marked histopathological lesions in the testes were recorded at 4 mg/kg/day. Global transcriptomic analysis of rat testes revealed cell cycle and cell death as the major biological processes affected. In particular, we identified an alteration in the expression of genes associated with cell cycle progression (mitotic roles of polo-like kinase). Dinitrobenzene was administered in suspension to rats (7 weeks old at start of treatment) by oral gavage at a daily dose of 0 (control, 0.5% methylcellulose in sterilized water), 0.1, 1, and 4 mg/kg body weight, for 4 consecutive days. Dose-related changes in gene expression were determined in the testes using whole genome oligonucleotide microarrays.

2012-07-13 | E-GEOD-39344 | biostudies-arrayexpress

Control of lateral root formation by rapamycin-induced dimerization of engineered RGI/BAK1 and by BIR3 chimera

Project description:Leucine-rich repeat receptor kinases (LRR-RKs) play a pivotal role in diverse aspects of growth, development, and immunity in plants by sensing extracellular signals. Typically, LRR-RKs are activated through the ligand-induced interaction with a SOMATIC EMBRYOGENESIS RECEPTOR KINASE (SERK) coreceptor, triggering downstream signaling. ROOT MERISTEM GROWTH FACTOR1 (RGF1) INSENSITIVEs (RGIs) LRR-RLK receptors promote primary root meristem activity while inhibiting lateral root (LR) development in response to RGF peptide. In this study, we employed rapamycin-induced dimerization (RiD) and BAK1-INTERACTING RECEPTOR-LIKE KINASE3 (BIR3) chimera approaches to explore the gain-of-function of RGI1, RGI4, and RGI5. Rapamycin induced the association of cytosolic kinase domains (CKDs) of RGI1 and the BAK1 coreceptor, activating both mitogen-activated protein kinase 3 (MPK3) and MPK6. Rapamycin significantly inhibited LR formation in RiD-RGI1/RGI4/RGI5-BAK1 plants. Using transgenic Arabidopsis expressing RGI1CKD fused to the BIR3-LRR chimera under estradiol control, we observed a substantial reduction in LR density upon β-estradiol treatment. Additionally, we identified a decrease in root gravitropism in BIR3 chimera plants. In contrast, RiD-RGI/BAK1 plants did not exhibit defects in root gravitropism, implying the importance of combinatorial interactions between RGIs and SERK coreceptors in the inhibition of root gravitropism. Constitutive activation of RGIs with BAK1 in RiD-RGI/BAK1 plants by rapamycin treatment resulted in the inhibition of primary root growth, resembling the inhibitory effects observed with high concentrations of phytohormones on primary root elongation. Our findings highlight that the interactions between CKDs of RGIs and BAK1, constitutively induced by rapamycin or BIR3 chimera, efficiently control LR development.

2023-12-21 | GSE138627 | GEO

Combined absence of Trp53 target genes Zmat3, Puma and p21 cause a high incidence of cancer in mice

Project description:Transcriptional activation of target genes is essential for TP53-mediated tumour suppression, though the roles of the diverse TP53-activated target genes in tumour suppression remains poorly understood. Knockdown of Zmat3, an RNA-binding zinc-finger protein involved in regulating alternative splicing, in haematopoietic cells by shRNA caused leukaemia only with the concomitant absence of the Puma and p21, the critical effectors of Trp53-mediated apoptosis and cell cycle arrest respectively. We were interested to further investigate the role of ZMAT3 in tumour suppression beyond the haematopoietic system. Therefore, we generated Zmat3 knockout and compound gene knockout mice, lacking Zmat3 and p21, Zmat3 and Puma or all three genes. Puma-/-p21-/-Zmat3-/- triple knockout mice developed tumours at a significantly higher frequency compared to wild-type, Puma-/-Zmat3-/- or p21-/-Zmat3-/-deficient mice. Interestingly, we observed that the triple knockout and Puma-/-Zmat3-/- double deficient animals succumbed to lymphoma, while p21-/-Zmat3-/- animals developed mainly solid cancers. This analysis suggests that in addition to ZMAT3 loss, additional TRP53-regulated processes must be disabled simultaneously for TRP53-mediated tumour suppression to fail. Our findings reveal that the absence of different TRP53 regulated tumour suppressive processes changes the tumour spectrum, indicating that different TRP53 tumour suppressive pathways are more critical in different tissues.

2023-11-28 | GSE248747 | GEO

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