Notch/HES1-mediated PARP1 activation: a cell type-specific mechanism for tumor suppression
Notch/HES1-mediated PARP1 activation: a cell type-specific mechanism for tumor suppression
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DOI：
10.1182/blood-2009-12-253419
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发表时间：
2011-03-10
期刊：
影响因子：
20.3
通讯作者：
Zweidler-McKay, Patrick A.
中科院分区：
文献类型：
--
作者：
Kannan, Sankaranarayanan;Fang, Wendy;Zweidler-McKay, Patrick A.
Noch信号既发挥致癌作用，又发挥肿瘤抑制作用，这取决于细胞类型。与T细胞急性淋巴细胞白血病(ALL)不同，Notch激活促进了白血病的发生，而B细胞ALL(B-ALL)中Notch信号的诱导会导致生长停滞和细胞凋亡。Split1的Notch靶向毛发/增强子(HES1)足以在B-ALL中复制这种肿瘤抑制表型；然而，其机制尚不清楚。我们报道了HES1通过一种新的相互作用蛋白Poly ADP-Ribose Polymerase1(PARP1)以细胞类型特异性的方式调节促凋亡信号。HES1与PARP1的相互作用抑制了HES1的功能，诱导了PARP1的激活，并导致B-ALL中PARP1的切割。HES1诱导的PARP1活化导致PARP1的自身ADP核糖化，烟酰胺腺嘌呤二核苷酸(+)的消耗，三磷酸腺苷水平的降低，以及凋亡诱导因子从线粒体到细胞核的移位，导致B-ALL而不是T细胞ALL的凋亡。重要的是，Notch激动肽Delta/Serrate/Lag-2诱导的Notch信号可以重现这些事件，并导致B-ALL细胞凋亡。HES1和PARP1在B-ALL中的新的相互作用通过PARP1调节HES1转录复合体的功能和信号诱导细胞凋亡。这一机制显示了一种细胞类型特异性的促凋亡途径，可能导致以Notch激动剂为基础的癌症治疗。(血。2011；117(10)：2891-2900)
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. (Blood. 2011;117(10):2891-2900)