Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA136887 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Notch signaling plays both oncogenic and tumor suppressor roles, depending on cell type. In contrast to T cell acute lymphoblastic leukemia (T-ALL), where Notch activation promotes leukemogenesis, induction of Notch signaling in B-ALL leads to growth arrest and apoptosis. The Notch target Hairy/Enhancer of Split1 (HES1) is sufficient to reproduce this tumor suppressor phenotype in B-ALL, however the mechanism is not yet known. Here we report that HES1 regulates pro-apoptotic signals via the novel interacting protein Poly ADP-Ribose Polymerase1 (PARP1) in a cell type-specific manner. The interaction of HES1 with PARP1 inhibits HES1 function, induces PARP1 activation and results in PARP1 cleavage in B-ALL. HES1-induced PARP1 activation leads to self-ADP ribosylation of PARP1, consumption of NAD+, diminished ATP levels, and translocation of the Apoptosis Inducing Factor (AIF) from mitochondria to the nucleus, resulting in apoptosis in B-ALL, but not T-ALL. Importantly, induction of Notch signaling via the Notch agonist peptide DSL can reproduce these events and leads to BALL apoptosis. The novel interaction of HES1 and PARP1 in B-ALL modulates the function of the HES1 transcriptional complex and signals through PARP1 to induce apoptosis. This mechanism reveals a cell type-specific pro-apoptotic pathway which may lead to Notch agonist-based cancer therapeutics. Study involved the gene expression profiling of human acute lymphoblastic leukemia samples, and comparison of the levels of expression NOTCH1 pathway genes and targets across ALL subtypes
2011-12-12 | E-GEOD-26366 | biostudies-arrayexpress
Project description:Notch signaling plays both oncogenic and tumor suppressor roles, depending on cell type. In contrast to T cell acute lymphoblastic leukemia (T-ALL), where Notch activation promotes leukemogenesis, induction of Notch signaling in B-ALL leads to growth arrest and apoptosis. The Notch target Hairy/Enhancer of Split1 (HES1) is sufficient to reproduce this tumor suppressor phenotype in B-ALL, however the mechanism is not yet known. Here we report that HES1 regulates pro-apoptotic signals via the novel interacting protein Poly ADP-Ribose Polymerase1 (PARP1) in a cell type-specific manner. The interaction of HES1 with PARP1 inhibits HES1 function, induces PARP1 activation and results in PARP1 cleavage in B-ALL. HES1-induced PARP1 activation leads to self-ADP ribosylation of PARP1, consumption of NAD+, diminished ATP levels, and translocation of the Apoptosis Inducing Factor (AIF) from mitochondria to the nucleus, resulting in apoptosis in B-ALL, but not T-ALL. Importantly, induction of Notch signaling via the Notch agonist peptide DSL can reproduce these events and leads to BALL apoptosis. The novel interaction of HES1 and PARP1 in B-ALL modulates the function of the HES1 transcriptional complex and signals through PARP1 to induce apoptosis. This mechanism reveals a cell type-specific pro-apoptotic pathway which may lead to Notch agonist-based cancer therapeutics.
2011-12-12 | GSE26366 | GEO
Project description:We investigated the mechanism of suppression of Notch during efferocytosis. Genetically activation of Notch or ablation of Rubicon in marophages induced pro-inflammatory polarization and enhance anti-tumor effect.
2026-01-08 | GSE283549 | GEO
Project description:We investigated the mechanism of suppression of Notch during efferocytosis. Genetically activation of Notch or ablation of Rubicon in marophages induced pro-inflammatory polarization and enhance anti-tumor effect.
2026-01-08 | GSE283548 | GEO
Project description:We investigated the mechanism of suppression of Notch during efferocytosis. Genetically activation of Notch or ablation of Rubicon in marophages induced pro-inflammatory polarization and enhance anti-tumor effect.
2026-01-08 | GSE283547 | GEO
Project description:In leukemogenesis Notch signaling can be up- and down-regulated in a context-dependent manner. Here we report that deletion of hairy and enhancer of split-1 (Hes1) promotes acute myeloid leukemia (AML) development induced by the MLL-AF9 fusion protein. Subsequently, the FMS-like tyrosine kinase 3 (FLT3) was up-regulated in mouse cells of a Hes1- or RBP-J-null background. MLL-AF9-expressing Hes1-null AML cells showed enhanced proliferation and ERK phosphorylation following FLT3 ligand stimulation. FLT3 inhibition efficiently abrogated proliferation of MLL-AF9-induced Hes1-null AML cells. Furthermore, an agonistic anti-Notch2 antibody induced apoptosis of MLL-AF9-induced AML cells in a Hes1-wild type but not a Hes1-null background. These observations demonstrate that Hes1 mediates tumor suppressive roles of Notch signaling in AML development by down-regulating FLT3 expression. 4 samples are analyzed, two pairs of MLL-AF9/Hes1-/- and MLL-AF9/Hes1+/+ leukemic bone marrows.
2017-05-02 | E-GEOD-50234 | biostudies-arrayexpress
Project description:Hes1 is responsible for Notch signaling-mediated suppression of acute myeloid leukemia development
| PRJNA217323 | ENA
Project description:In leukemogenesis Notch signaling can be up- and down-regulated in a context-dependent manner. Here we report that deletion of hairy and enhancer of split-1 (Hes1) promotes acute myeloid leukemia (AML) development induced by the MLL-AF9 fusion protein. Subsequently, the FMS-like tyrosine kinase 3 (FLT3) was up-regulated in mouse cells of a Hes1- or RBP-J-null background. MLL-AF9-expressing Hes1-null AML cells showed enhanced proliferation and ERK phosphorylation following FLT3 ligand stimulation. FLT3 inhibition efficiently abrogated proliferation of MLL-AF9-induced Hes1-null AML cells. Furthermore, an agonistic anti-Notch2 antibody induced apoptosis of MLL-AF9-induced AML cells in a Hes1-wild type but not a Hes1-null background. These observations demonstrate that Hes1 mediates tumor suppressive roles of Notch signaling in AML development by down-regulating FLT3 expression.
2017-05-02 | GSE50234 | GEO
Project description:Notch signaling regulates several cellular processes including cell fate decisions and proliferation in both invertebrates and mice. However, comparatively less is known about the role of Notch during early human development. Here, we examined the function of Notch signaling during hematopoietic lineage specification from human pluripotent stem cells (hPSCs) of both embryonic and adult fibroblast origin. Using immobilized Notch ligands and siRNA to Notch receptors we have demonstrated that Notch1, but not Notch2 activation, induced HES1 expression and generation of committed hematopoietic progenitors. Using gain and loss of function approaches, this was shown to be attributed to Notch signaling regulation through HES1, that dictated cell fate decisions from bipotent precursors either to the endothelial or hematopoietic lineages at the clonal level. Our study reveals a previously unappreciated role for the Notch pathway during early human hematopoiesis, whereby Notch signaling via HES1 represents a toggle switch of hematopoietic vs. endothelial fate specification.
2013-06-01 | GSE47466 | GEO
Project description:YAP1 is participated in numerous biological processes including organ size control and tissue homeostasis. We previously reported that abnormal YAP1 activation accounted for the malignant characteristics of breast cancer, including stemness, metastasis and drug resistance. However, as a transcription coregulator, YAP1 was generally considered to be an undruggable target, which limits its further clinical application. Here, using co-immunoprecipitation and mass spectrometry analysis, we identified PARP1 as a novel regulator in the control of YAP1-TEAD4 transcriptional activity, breast cancer cell stemness, metastasis and immune evasion, which was independent on DNA damage response. Specifically, we found PARP1 directly interacted with YAP1-TEAD4 complex and enhanced their interactions through PARP1-mediated TEAD4 PARylation at a novel conserved R108K109 site. Moreover, PARP1-mediated YAP1-TEAD4 binding attenuated YAP1 interaction with CRL4DCAF12, and thus prevented YAP1 ubiquitination and degradation in cell nucleus. In addition, expression levels of PARP1 correlate with YAP1 and PD-L1 protein levels in breast cancer patient tissues and cells. Accordingly, simultaneous inhibition of PARP1 activity and blockade of PD-L1 enhanced CD8+/CD4+ cytolytic and tumor suppression functions in vivo. Overall, our findings not only reveal a new regulatory mechanism for PARP1-mediated YAP1-TEAD4 transcriptional activity, but also provide translational implications of targeting PARP1 for YAP1-TEAD4 complex-based anti-tumor therapy.
2025-09-26 | PXD068941 |