hes1-protein--human and Precursor-B-Cell-Lymphoblastic-Leukemia-Lymphoma

Notch signaling plays both oncogenic and tumor suppressor roles, depending on cell type. In contrast to T-cell acute lymphoblastic leukemia (ALL), where Notch activation promotes leukemogenesis, induction of Notch signaling in B-cell ALL (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. We report that HES1 regulates proapoptotic signals by the novel interacting protein Poly ADP-Ribose Polymerase1 (PARP1) in a cell type-specific manner. 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 nicotinamide adenine dinucleotide(+), diminished adenosine triphosphate levels, and translocation of apoptosis-inducing factor from mitochondria to the nucleus, resulting in apoptosis in B-ALL but not T-cell ALL. Importantly, induction of Notch signaling by the Notch agonist peptide Delta/Serrate/Lag-2 can reproduce these events and leads to B-ALL 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 shows a cell type-specific proapoptotic pathway that may lead to Notch agonist-based cancer therapeutics.

Topics: Apoptosis; Basic Helix-Loop-Helix Transcription Factors; Cell Line, Tumor; Cell Separation; Child; Chromatin Immunoprecipitation; Enzyme Activation; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Genes, Tumor Suppressor; Homeodomain Proteins; Humans; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Receptors, Notch; RNA, Messenger; Signal Transduction; Transcription Factor HES-1; Transfection