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.
Notch/HES1-mediated PARP1 activation: a cell type-specific mechanism for tumor suppression.
Specimen part
View SamplesVasoregression is a hallmark of vascular eye diseases but the mechanisms involved are still largely unknown. We have recently characterized a rat ciliopathy model which develops primary photoreceptor degeneration and secondary vasoregression. To improve the understanding of secondary vasoregression in retinal neurodegeneration, we used microarray techniques to compare gene expression profiles in this new model before and after retinal vasoregression. Differential gene expression was validated by quantitative RT-PCR, Western blot and immunofluorescence. Of the 374 genes regulated more than twofold, the MHC class II invariant chain CD74 yielded the strongest upregulation, and was allocated to activated microglial cells close to the vessels undergoing vasoregression. Pathway clustering identified genes of the immune system, inflammatory signaling, and components of the complement cascade upregulated during vasoregression. Furthermore, macroglial cells were markedly activated. Together, our data suggest that glial cells involved in retinal immune response participate in the initiation of vasoregression in the retina.
Gene expression profiling of vasoregression in the retina--involvement of microglial cells.
Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Immunopathology of childhood celiac disease-Key role of intestinal epithelial cells.
Specimen part, Cell line, Treatment
View SamplesComparison of laminin binding and laminin non-binding germ cells
Defining the spermatogonial stem cell.
No sample metadata fields
View SamplesRat germ cells
Defining the spermatogonial stem cell.
No sample metadata fields
View SamplesAnalysis of the influence of celiac disease-associated bacteria and gluten on intestinal epithelial cells
Immunopathology of childhood celiac disease-Key role of intestinal epithelial cells.
Cell line, Treatment
View SamplesAnalysis of the influence of celiac disease-associated bacteria and gluten on intestinal epithelial cells
Immunopathology of childhood celiac disease-Key role of intestinal epithelial cells.
Cell line, Treatment
View SamplesAnalysis of the influence of celiac disease-associated bacteria on intestinal epithelial cells
Immunopathology of childhood celiac disease-Key role of intestinal epithelial cells.
Cell line, Treatment
View SamplesAnalysis of role of small intestinal intraepithelial lymphocytes (IELs) in the immunopathology of celiac disease
Immunopathology of childhood celiac disease-Key role of intestinal epithelial cells.
Specimen part
View SamplesAnalysis of role of small intestinal epithelial cells (IECs) in the immunopathology of celiac disease
Immunopathology of childhood celiac disease-Key role of intestinal epithelial cells.
Specimen part
View Samples