Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA181347 | ENA |
REPOSITORIES: ENA
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Project description:ING proteins play an essential role in the control of a variety of cellular functions whose deregulation is associated with tumor formation and dissemination, such as proliferation, apoptosis, senescence or invasion. Accordingly, loss of function of ING proteins is a frequent event in many types of human tumors. In this report, we have studied the function of ING4, a member of the ING family of tumor suppressors, in the context of normal, non-transformed primary fibroblasts. We show that ING4 negatively regulates cell proliferation in this cell type. The antiproliferative action of ING4 requires its ability to recognize chromatin marks, it is p53-dependent and it is lost in an ING4 cancer-associated mutant. Gene expression analysis shows that ING4 regulates the expression and release of soluble factors of the chemokine family. The secretory phenotype regulated by ING4 in primary fibroblasts displays a selective paracrine effect on proliferation, fostering the division of tumor cells, while inhibiting division in primary fibroblasts. Consistently, ING4-expressing fibroblasts promoted tumor growth in vivo in co-injection tumorigenesis assays. Collectively, our results show that ING4 not only can regulate the proliferation of primary non-transformed human fibroblasts, but also orchestrates a secretory phenotype in these cells that promotes tumor cell proliferation in vitro and in vivo. These findings support a critical role for ING4 expression in normal cells in the non-cell autonomous regulation of tumor growth. Gene expression analysis shows that ING4 regulates the expression and release of soluble factors of the chemokine family. Two independent retroviral infections were performed in early pasaje IMR-90 fibroblasts with wild-type ING4 wild type and the N214D mutant. All of them were hibridazed by duplicate againts a reference sample from vector-infected cells
2013-04-22 | E-GEOD-42412 | biostudies-arrayexpress
Project description:ING proteins play an essential role in the control of a variety of cellular functions whose deregulation is associated with tumor formation and dissemination, such as proliferation, apoptosis, senescence or invasion. Accordingly, loss of function of ING proteins is a frequent event in many types of human tumors. In this report, we have studied the function of ING4, a member of the ING family of tumor suppressors, in the context of normal, non-transformed primary fibroblasts. We show that ING4 negatively regulates cell proliferation in this cell type. The antiproliferative action of ING4 requires its ability to recognize chromatin marks, it is p53-dependent and it is lost in an ING4 cancer-associated mutant. Gene expression analysis shows that ING4 regulates the expression and release of soluble factors of the chemokine family. The secretory phenotype regulated by ING4 in primary fibroblasts displays a selective paracrine effect on proliferation, fostering the division of tumor cells, while inhibiting division in primary fibroblasts. Consistently, ING4-expressing fibroblasts promoted tumor growth in vivo in co-injection tumorigenesis assays. Collectively, our results show that ING4 not only can regulate the proliferation of primary non-transformed human fibroblasts, but also orchestrates a secretory phenotype in these cells that promotes tumor cell proliferation in vitro and in vivo. These findings support a critical role for ING4 expression in normal cells in the non-cell autonomous regulation of tumor growth. Gene expression analysis shows that ING4 regulates the expression and release of soluble factors of the chemokine family.
2013-04-22 | GSE42412 | GEO
Project description:Aberrations in chromatin dynamics play a fundamental role in tumorigenesis, yet relatively little is known of the molecular mechanisms linking histone lysine methylation to neoplastic disease. ING4 (Inhibitor of Growth 4) is a native subunit of an HBO1 histone acetyltransferase (HAT) complex and a tumor suppressor protein. Here we show a critical role for the specific read-out of histone H3 trimethylated at lysine 4 (H3K4me3) by the ING4 PHD finger in mediating ING4 gene expression and tumor suppressor functions. The interaction between ING4 and H3K4me3 augments the acetylation activity of HBO1 on H3 tails, and drives H3 acetylation at ING4 target promoters to effect a DNA damage-dependent gene expression program. Further, ING4 facilitates apoptosis in response to genotoxic stress and inhibits anchorage-independent cell growth, and these functions are dependent on ING4 interactions with H3K4me3. Together, our results demonstrate a mechanism for brokering crosstalk between H3K4 methylation and histone H3 acetylation, and reveal a new molecular link between chromatin modulation and tumor suppressor mechanisms. ING4 ChIP-chip +/- Doxorubicin treatment in HT1080 cells on Nimblegen whole genome promoter array 4 samples: HT1080 cell lines stably expressing Flag-ING4 or Flag-ING4-D213A, +/- doxorubicin
2010-05-17 | E-GEOD-13412 | biostudies-arrayexpress
Project description:Aberrations in chromatin dynamics play a fundamental role in tumorigenesis, yet relatively little is known of the molecular mechanisms linking histone lysine methylation to neoplastic disease. ING4 (Inhibitor of Growth 4) is a native subunit of an HBO1 histone acetyltransferase (HAT) complex and a tumor suppressor protein. Here we show a critical role for the specific read-out of histone H3 trimethylated at lysine 4 (H3K4me3) by the ING4 PHD finger in mediating ING4 gene expression and tumor suppressor functions. The interaction between ING4 and H3K4me3 augments the acetylation activity of HBO1 on H3 tails, and drives H3 acetylation at ING4 target promoters to effect a DNA damage-dependent gene expression program. Further, ING4 facilitates apoptosis in response to genotoxic stress and inhibits anchorage-independent cell growth, and these functions are dependent on ING4 interactions with H3K4me3. Together, our results demonstrate a mechanism for brokering crosstalk between H3K4 methylation and histone H3 acetylation, and reveal a new molecular link between chromatin modulation and tumor suppressor mechanisms.
2008-11-05 | GSE13412 | GEO
Project description:Tumor cells with diverse phenotype and biological behaviors are influenced by stromal cells through secretory factors or direct cell-cell contact. Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive desmoplasia with fibroblasts as the major cell type. Here, we observed enrichment of myofibroblasts in juxta-tumoral position, where tumor cells gain epithelial-mesenchymal transition for invasion, that correlated with worsened prognosis in PDAC patients. Direct cell-cell contacts as forming heterocellular aggregates between fibroblasts and tumor cells were detected in primary pancreatic tumors and circulating tumor microemboli. Mechanistically, the overexpressed ATP1A1 of tumor cells binds to and reorganizes ATP1A1 of fibroblasts inducing calcium oscillations, NF-κB activation, and activin A secretion. Consequentially, either silencing ATP1A1 expression or neutralizing activin A secretion suppresses tumor invasion and colonization. Taken together, these results elucidate the mechanic interplay between tumor cells and the bound fibroblasts in PDAC progression, and provide opportunities for potential therapeutic strategy against tumor metastasis by blocking such interaction.
2022-06-09 | PXD029467 | Pride
Project description:C/EBPβ is an important regulator of oncogene-induced senescence (OIS). Here we show that C/EBPγ, a heterodimeric partner of C/EBPβ whose biological functions are not well understood, inhibits cellular senescence. Cebpg-/- MEFs proliferated poorly, entered senescence prematurely, and expressed a pro-inflammatory gene signature, including elevated levels of senescence-associated secretory phenotype (SASP) genes whose induction by oncogenic stress requires C/EBPβ. The senescence-suppressing activity of C/EBPγ required its ability to heterodimerize with C/EBPβ. Covalently linked C/EBPβ homodimers (β~β) inhibited the proliferation and tumorigenicity of RasV12-transformed NIH3T3 cells, activated SASP gene expression, and recruited the CBP co-activator in a Ras-dependent manner, whereas γ~β heterodimers lacked these capabilities and efficiently rescued proliferation of Cebpg-/- MEFs. C/EBPβ depletion partially restored growth of C/EBPγ-deficient cells, indicating that the increased levels of C/EBPβ homodimers in Cebpg-/- MEFs inhibit proliferation. The proliferative functions of C/EBPγ are not restricted to fibroblasts, as hematopoietic progenitors from Cebpg-/- bone marrow also displayed impaired growth. Furthermore, high CEBPG expression correlated with poorer clinical prognoses in several human cancers, and C/EBPγ depletion decreased proliferation and induced senescence in lung tumor cells. Our findings demonstrate that C/EBPγ neutralizes the cytostatic activity of C/EBPβ through heterodimerization, which prevents senescence and suppresses basal transcription of SASP genes. Mouse embryonic fibroblasts were isolated at E13.5 and propagated. At passage 3 cells were plated with equal density and collected 48 hours later.
2013-06-30 | E-GEOD-47777 | biostudies-arrayexpress
Project description:Cancer-associated fibroblasts (CAFs) are key contributors to ovarian cancer (OC) progression and therapeutic resistance through dysregulation of the extracellular matrix (ECM). CAFs are a heterogenous population derived from different cell types through activation and reprogramming. Current studies rely on uncharacterized heterogenous primary CAFs or normal fibroblasts that fail to recapitulate CAF-like tumor behavior. Here, we present that conditioned media from ovarian cancer lines leads to an increase in the activated state of fibroblasts demonstrated by functional assays and up-regulation of known CAF-related genes and ECM pathways. Phenotypic and functional characterization demonstrated that the conditioned CAFs expressed a CAF-like phenotype, strengthened proliferation, secretory, contractility, and ECM remodeling properties when compared to resting normal fibroblasts, consistent with an activated fibroblast status. Moreover, conditioned CAFs significantly enhanced drug resistance and tumor progression. Critically, the conditioned CAFs resemble a transcriptional signature with involvement of ECM remodeling. The present study provides mechanistic and functional insights about the activation and reprogramming of CAFs in the ovarian tumor microenvironment mediated by nonvesicular paracrine signaling. Moreover, it provides a translational based approach to reprogram normal fibroblasts from both uterine and ovarian origin into CAFs using tumor-derived conditioned media. Using these resources, further development of therapeutics that possess potentiality and specificity towards CAF/ECMmediated chemoresistance in OC are further warranted.
2024-10-30 | GSE280564 | GEO
Project description:The lncRNA MIR31HG regulates the senescence associated secretory phenotype
| PRJNA604779 | ENA
Project description:In previous investigations, we detected that growth of melanoma cells in mice depleted for adam9 is enhanced. This resulted from molecular alterations in stromal cells cross-communicating to tumor cells and from constitutively altered expression of some molecules, e.g., TIMP1 in stromal fibroblasts lacking adam9. We used microarray analysis to identify the gene expression alterations occurring in stromal cells upon adam9 deletion which lead to the molecular alterations observed and contribute to the tumor phenotype. Primary fibroblasts from adam9 KO and WT mice were cultured in standard conditions to address constitutive gene alterations.
2014-03-28 | E-GEOD-56304 | biostudies-arrayexpress
Project description:Inhibitor of growth 4 and 5 (ING4 and ING5) are chromatin-binding proteins in the KAT6A, KAT6B and KAT7 histone acetyltransferase protein complexes. Heterozygous mutations in the KAT6A or KAT6B gene cause human disorders with cardiac defects, but the contribution of their chromatin adaptor proteins to development is unknown. We found that Ing5–/– mice had isolated cardiac ventricular septal defects. ING4 and ING5 are structurally similar proteins, suggesting a degree of redundancy. Combined loss of ING4 and ING5 caused developmental arrest at embryonic day E8.5, loss of histone H3 lysine 14 acetylation (H3K14ac), a reduction in H3K23ac levels and disruption of developmental gene expression in Ing4–/–Ing5–/– compared to control embryos. E12.5 Ing4+/–Ing5–/– hearts showed a paucity of epicardial cells and epicardium-derived cells, failure of myocardium compaction and coronary vasculature defects, accompanied by a reduction in the expression of epicardium genes compared to control hearts. In addition, a reduction in the expression of genes required for cell adhesion, both in whole E8.75 Ing4–/–Ing5–/– embryos and in E10.5 Ing4+/–Ing5–/– hearts compared to controls was observed. In vitro assessment of fibroblast and proepicardium explants revealed cell spreading and outgrowth defects. Our findings suggest that ING4 and ING5 are essential for heart development and promote epicardium and epicardium-derived cell fates and mutation of the human ING5 gene as a possible cause of isolated ventricular septal defects.
2024-02-01 | GSE252338 | GEO