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Notch/HES1-mediated PARP1 activation: A cell-type specific mechanism for tumor suppression

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE26366 | GEO | 2011/12/12

SECONDARY ACCESSION(S): PRJNA136887

REPOSITORIES: GEO

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Notch/HES1-mediated PARP1 activation: A cell-type specific mechanism for tumor suppression

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

Hes1 is responsible for Notch signaling-mediated suppression of acute myeloid leukemia development

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

Hes1 is responsible for Notch signaling-mediated suppression of acute myeloid leukemia development

2017-05-02 | GSE50234 | GEO

Poly (ADP-Ribose) Polymerase 1 Regulates Cajal-Retzius Cell Development and Neural Precursor Cell Adhesion

Project description:Poly (ADP-Ribose) Polymerase 1 (PARP1) is a ubiquitously expressed enzyme that regulates DNA damage repair, cell death, inflammation, and transcription. PARP1 functions by adding ADP-ribose polymers (PAR) to proteins including itself, using NAD+ as a donor. This post-translational modification known as PARylation results in changes in the activity of PARP1 and its substrate proteins and has been linked to the pathogenesis of various neurological diseases. PARP1 KO mice display schizophrenia-like behaviors, have impaired memory formation, and have defects in neuronal proliferation and survival, while mutations in genes that affect PARylation have been associated with intellectual disability, psychosis, neurodegeneration, and stroke in humans. Yet, the roles of PARP1 in brain development have not been extensively studied. We now find that loss of PARP1 leads to defects in brain development and increased neuronal density at birth. We further demonstrate that PARP1 loss increases the expression levels of genes associated with neuronal migration and adhesion in the E15.5 cerebral cortex, including Reln. This correlates with an increased number of Cajal-Retzius (CR) cells in vivo and in cultures of embryonic neural progenitor cells (NPCs) derived from the PARP1 KO cortex. Furthermore, PARP1 loss leads to increased NPC adhesion to N-cadherin, like that induced by experimental exposure to Reelin. Taken together, these results uncover a novel role for PARP1 in brain development, i.e., regulation of CR cells, neuronal density, and cell adhesion.

2021-09-16 | GSE171852 | GEO

Transcriptional reprogramming and resistance to colonic mucosal injury in PARP1-deficient mice

Project description:Poly(ADP-ribose) polymerases (PARPs) synthesize and bind branched polymers of ADP-ribose to acceptor proteins using NAD as a substrate, and participate to the control of gene transcription and DNA repair. PARP1, the most abundant isoform, regulates the expression of proinflammatory mediator - cytokines, chemokines and adhesion molecules, and inhibition of PARP1 enzymatic activity reduced or ameliorated autoimmune diseases in several experimental models, including colitis. However, the mechanism(s) underlying the protective effects of PARP1 inhibition in colitis and the cell types in which Parp1 deletion has the most significant impact are unknown. The objective of the current study was to determine the impact of Parp1 deletion on the innate immune response to mucosal injury. Genome-wide analysis of the colonic transcriptome was performed. Compared to WT, we demonstrated that Parp1-/-were protected from DSS-induced colitis and that this protection was associated with a dramatic transcriptional reprogramming in the colon. WT or Parp1-/- mice were treated with drinking water administered ad libitum without ot with 4% dextran sulfate (DSS) for seven days. Whole colon was collected for RNA extraction and hybridization on Affymetrix microarrays. Thee mice from each genotype/treatment groups were used in the analysis.

2016-01-08 | E-GEOD-76658 | biostudies-arrayexpress

Transcription profiling of human T cell leukaemia cell line Jurkat that were retrovirally transduced with constitutievely active forms of Notch to identify novel transcriptional targets of Notch signalling

Project description:In this study we aimed to identify novel transcriptional targets of Notch signalling in the T cell leukaemia cell line, Jurkat. RNA was prepared from Jurkat cells retrovirally transduced with an empty vector (Mock) or vectors containing constitutively active forms of Notch (N1deltaE or N3deltaE), and used for Affymetrix microarray analysis. As expected, several known transcriptional target of Notch, such as HES1 and HERP2, were found to be overexpressed in Notch-transduced cells, however, many novel transcriptional targets of Notch signalling were identified using this approach. These included the T cell costimulatory molecule CD28, the anti-apoptotic protein GIMAP5, and inhibitor of DNA binding 1 (1D1).

2009-07-15 | E-MEXP-1744 | biostudies-arrayexpress

Poly ADP-ribosylation of SET8 leads to aberrant H4K20 methylation domains in mammalian cells

Project description:In mammalian cells, SET8 mediated Histone H4 Lys 20 monomethylation (H4K20me1) has been implicated in regulating mitotic condensation, DNA replication, DNA damage response, and gene expression. Here we show SET8, the only known enzyme for H4K20me1 is post-translationally poly ADP-ribosylated by PARP1 on lysine residues. PARP1 interacts with SET8 in a cell cycle- dependent manner. Poly ADP-ribosylation on SET8 renders it catalytically compromised and it undergoes degradation via ubiquitylation pathway. Knockdown of PARP1 shifted the relative dynamic equilibrium of H4K20me2 to H4K20me3 in cells. Overexpression or knockdown of PARP1 led to aberrant H4K20me1 domains genome-wide, impacting Wnt signaling pathways genes and transcription factor binding site enrichment. Therefore, SET8 mediated chromatin remodeling in mammalian cells are influenced by poly ADP-ribosylation by PARP1.

2022-11-17 | GSE188744 | GEO

IGR_Michels_PARP

Project description:Non-small cell lung cancer (NSCLC) is often treated with cisplatin (CDDP). Here, we report that two distinct poly(ADP-ribose) polymerase (PARP) inhibitors exhibited a hyperadditive combination effect with CDDP to kill NSCLC cells. A majority of CDDP-resistant cell lines and clones exhibited constitutively increased PARP expression and enzymatic activity. Cells with hyperactivated PARP initiated a DNA damage response and the intrinsic pathway of apoptosis in response to pharmacological PARP inhibition or PARP1-targeting siRNAs. Transcriptome analysis depicted an unsupervised hierarchical clustering of NSCLC cells and CDDP resistant counterparts regarding to their response to PARP inhibitors. PARP-overexpressing tumors displayed elevated levels of intracellular poly(ADP-ribose) (PAR), which predicted the response to PARP inhibitors in vitro and in vivo more accurately than PARP expression itself. Thus, CDDP-resistant cancer cells develop a dependency to PARP, becoming susceptible to PARP inhibitor-induced apoptosis.

2013-10-31 | E-MTAB-1353 | biostudies-arrayexpress

RNA-seq of Pdx1-GFP+ sorted E10.5, wildtype and Hes1-/-. Neurog3-dependent Pancreas Dysgenesis Causes Ectopic Pancreas in Hes1 Mutants

Project description:RNA-seq of FACS Sorted E10.5 Pdx1-GFP+ of genotypes wildtype and Hes1-/-. Summary statement The developmental mechanisms that cause ectopic pancreas are poorly understood. We show that aberrant dorsal pancreas morphogenesis in Hes1 mutants leads to ectopic pancreas depending on the pro-endocrine gene Neurog3. Abstract Mutations in Hes1, a target gene of the Notch signalling pathway, lead to ectopic pancreas by a poorly described mechanism. Here we use genetic inactivation of Hes1 combined with lineage tracing in mouse embryos to reveal an endodermal requirement for Hes1 and that most ectopic pancreas tissue is derived from the E8.5 dorsal pancreas primordium. RNA-seq data from sorted E10.5 Pdx1-GFP+ cells from Hes1+/+ and Hes1−/− suggested that upregulation of endocrine lineage genes in Hes1−/− embryos was the major defect in the endoderm and accordingly early pancreas morphogenesis was normalised and the ectopic pancreas phenotype suppressed in Hes1−/−Neurog3−/− embryos. Analysis of other Notch pathway mutants uncovered a total depletion of progenitors in Mib1 deficient dorsal anlage, which was replaced by an anterior Gcg+ extension. Together, our results demonstrate that aberrant morphogenesis is the cause of ectopic pancreas and that a part of the endocrine differentiation program is mechanistically involved in the dysgenesis. Our results suggest that the ratio of endocrine lineage to progenitor cells is important for morphogenesis and that a strong endocrinogenic phenotype without complete progenitor depletion as seen in Hes1 mutants provokes an extreme dysgenesis that causes ectopic pancreas.

2018-08-20 | E-MTAB-6890 | biostudies-arrayexpress