Effector Caspases and Leukemia

Lu, Ying; Chen, Guoqiang

doi:10.1155/2011/738301

Cited by 20 publications

(19 citation statements)

References 102 publications

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“…Caspase-3 is a key protease activated during the early stages of apoptosis and, like other members of the caspase family, is synthesized as an inactive proenzyme that is processed in cells undergoing apoptosis by self-proteolysis and/or cleavage by another protease such as caspase 8 or 9 (Patel et al 1996). Caspase-7 is highly similar in structure (58%) and substrate-specificity to caspase-3, and caspases-3/7 are effector/executioner caspases (Lu and Chen 2011). Caspases 8 and 9 are also synthesized as inactive pro-caspases that are processed in cells undergoing apoptosis by self-proteolysis and/or cleavage by another protease (Patel et al 1996).…”

Section: Introductionmentioning

confidence: 99%

Mechanism of ziram-induced apoptosis in human T lymphocytes

Kobayashi

Kawada

2011

Arch Toxicol

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Ziram as a dithiocarbamate fungicide is widely used throughout the world in agriculture. We previously found that ziram significantly inhibited cytotoxic T lymphocyte activity in a dose-dependent manner. To explore the mechanism of this inhibition, we investigated ziram-induced apoptosis in human T lymphocytes. Jurkat T cells were treated with ziram at 0.031-1 μM for 2-24 h. Freshly isolated primary human T cells were treated with ziram at 0.0625-1 μM for 15 and 24 h. Apoptosis was determined by FITC-Annexin V/PI staining and the TUNEL assay. To explore the mechanism of apoptosis, intracellular levels of active caspases 3, 3/7, 8, and 9 and pan-caspase and mitochondrial cytochrome-c release were determined by flow cytometry. Disruption to mitochondrial transmembrane potential was determined with a MitoLight(™) Apoptosis Detection Kit. We found that ziram induced apoptosis in a time- and dose-dependent manner in both Jurkat cells and primary human T cells. The primary human T cells were more sensitive to ziram than the Jurkat cell line. Ziram induced increases in active caspases 3, 3/7, 8, and 9 and pan-caspase in a dose-dependent manner, and a caspase-3 inhibitor, Z-DEVD-FMK, partially but significantly inhibited the apoptosis. Moreover, a general caspase inhibitor, Z-VAD-FMK, significantly and almost completely blocked the apoptosis. Ziram also disrupted mitochondrial transmembrane potential and caused mitochondrial cytochrome-c release. These findings indicate that ziram can induce apoptosis in human T cells, and the apoptosis is mediated by both the caspase-cascade and the mitochondria/cytochrome-c pathways.

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Section: Introductionmentioning

confidence: 99%

Mechanism of ziram-induced apoptosis in human T lymphocytes

Kobayashi

Kawada

2011

Arch Toxicol

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“…Таким образом, можно предположить, что ме-ханизм действия реамберина связан с подавлением внеш-нерецепторного и р53-зависимого пути. Повышение ин-тенсивности синтеза каспазы-3 при введении Реамберина при нормальном уровне апоптоза может указывать на ее неапоптотическую функцию, что показано и другими авторами [11]. Примечание.…”

Section: результаты и обсуждениеunclassified

Role of Hepatoprotectors and Immunomodulators in Regulation of Hepatocyte Apoptosis Induced by Antituberculosis Treatment

Суханов

Бажанова²,

Teplyi³

2013

Annals RAMS

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It was currently shown that hepatopathy due to drug toxicity is associated with increased apoptosis of hepatocytes. Therefore, development of drugs which regulate cell death is of great importance. Aim: to involve some hepatoprotectors (ademethionine, reamberin, remaxol) and immunomodulators (cycloferon) into regulation of apoptosis in experimental models of liver first-line antituberculousis drugs (isoniazid, rifampicin, pyrazinamide). Materials and methods: levels of apoptosis (TUNEL), expression of CD95 (receptor of tumor necrosis factor -by immunohistochemistry), expression of

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“…[10][11][12][13] Caspase-3 has been found to be essential for normal brain development in some genetic mouse strains 14 ; however, Caspase-3-deficient mice are viable and fertile in the C57BL/6 strain with no apparent defects in brain pathology. 15,16 Caspase-3 has been shown to play important roles at multiple steps in embryonic stem cells and HSCs, affecting self-renewal and differentiation. [17][18][19] In the hematopoietic system, loss of Caspase-3 leads to accelerated proliferation and impaired differentiation of bone marrow cells.…”

Section: Introductionmentioning

confidence: 99%

“…24 We and others have shown that AE is a direct substrate of Caspase-3 and the cleavage sites are TMPD188 and LLLD368. 15,25,26 Moreover, a truncated AE protein (DAE), generated by cleavage of AE at Asp188, worked as a dominant-negative protein by interacting with AE and interfering with its oncogenic functions. 27,28 Together, these data suggest that AE may accumulate in a Caspase-3 compromised background and thereby accelerate leukemogenesis.…”

Section: Introductionmentioning

confidence: 99%

Caspase-3 controls AML1-ETO–driven leukemogenesis via autophagy modulation in a ULK1-dependent manner

Man

Tan

Sun

et al. 2017

Blood

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Key Points• Loss of Caspase-3 delays leukemogenesis in a mouse model for t(8;21) AML.• Loss of Caspase-3 triggers upregulation of ULK1 and induction of autophagy in leukemia-initiating cells.AML1-ETO (AE), a fusion oncoprotein generated by t(8;21), can trigger acute myeloid leukemia (AML) in collaboration with mutations including c-Kit, ASXL1/2, FLT3, N-RAS, and K-RAS. Caspase-3, a key executor among its family, plays multiple roles in cellular processes, including hematopoietic development and leukemia progression. Caspase-3 was revealed to directly cleave AE in vitro, suggesting that AE may accumulate in a Caspase-3-compromised background and thereby accelerate leukemogenesis. Therefore, we developed a Caspase-3 knockout genetic mouse model of AML and found that loss of Caspase-3 actually delayed AML1-ETO9a (AE9a)-driven leukemogenesis, indicating that Caspase-3 may play distinct roles in the initiation and/or progression of AML. We report here that loss of Caspase-3 triggers a conserved, adaptive mechanism, namely autophagy (or macroautophagy), which acts to limit AE9a-driven leukemia. Furthermore, we identify ULK1 as a novel substrate of Caspase-3 and show that upregulation of ULK1 drives autophagy initiation in leukemia cells and that inhibition of ULK1 can rescue the phenotype induced by Caspase-3 deletion in vitro and in vivo. Collectively, these data highlight Caspase-3 as an important regulator of autophagy in AML and demonstrate that the balance and selectivity between its substrates can dictate the pace of disease. (Blood. 2017;129(20):2782-2792

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Effector Caspases and Leukemia

Cited by 20 publications

References 102 publications

Mechanism of ziram-induced apoptosis in human T lymphocytes

Mechanism of ziram-induced apoptosis in human T lymphocytes

Role of Hepatoprotectors and Immunomodulators in Regulation of Hepatocyte Apoptosis Induced by Antituberculosis Treatment

Caspase-3 controls AML1-ETO–driven leukemogenesis via autophagy modulation in a ULK1-dependent manner

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