Impaired thymic development in mouse embryos deficient in apoptotic DNA degradation

Kawane, Kohki; Fukuyama, Hidehiro; Yoshida, Hideyuki; Nagase, Hiroko; Ohsawa, Yoshiyuki; Uchiyama, Yasuo; Okada, Kazuhisa; Iida, Tetsuya; Nagata, Shinji

doi:10.1038/ni881

Cited by 211 publications

(218 citation statements)

References 50 publications

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“…1D). We also found that T cell blasts lacking caspase-activated DNase, which is an essential molecule for DNA fragmentation process (18), failed to undergo apoptosis even in the presence of LL-Z1640-2 (Fig. 2F).…”

Section: Blockade Of the Tak1 Signal Induces Apoptosis In Activated Tmentioning

confidence: 76%

TAK1–JNK Axis Mediates Survival Signal through Mcl1 Stabilization in Activated T Cells

Hirata

Sugie

Matsuda

et al. 2013

The Journal of Immunology

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TAK1, a member of MAPK kinase kinase (MAPKK-K) family, can activate JNK, p38 MAPK, and NF-κB signaling pathways. Although targeted gene disruption studies have demonstrated that TAK1 plays a critical role in T cell functions, precise functions of downstream mediators remain elusive. We used the chemical compound LL-Z1640-2, which preferentially suppressed MAPK activation but not NF-κB signal downstream of TAK1. LL-Z1640-2 blocked TCR-induced T cell proliferation and activation, confirming that a TAK1-mediated MAPK signal is essential for T cell activation. LL-Z1640-2 induced apoptosis of activated mouse splenic T cells in a caspase- and caspase-activated DNase–dependent manner. TAK1-JNK pathway, which is activated downstream of IL-2R, induced the phosphorylation of antiapoptotic protein Mcl1 in activated T cells, resulting in the stabilization of Mcl1 protein. Our data uncover that among signal transduction pathways downstream of TAK1, JNK mediates a survival program through Mcl1 stabilization downstream of IL-2R in activated T cells and that blockade of TAK1-JNK pathway can eliminate activated T cells by apoptosis.

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Section: Blockade Of the Tak1 Signal Induces Apoptosis In Activated Tmentioning

confidence: 76%

TAK1–JNK Axis Mediates Survival Signal through Mcl1 Stabilization in Activated T Cells

Hirata

Sugie

Matsuda

et al. 2013

The Journal of Immunology

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“…17 Among the candidates for nucleosomal DNA fragmentation, the role of CAD/DFF40 has been well documented in many apoptotic cases both in vivo and in vitro. [18][19][20] However, it remains controversial whether the apoptotic DNase is always the same or differs depending on cell types, differentiation state, and/or apoptotic stimuli.…”

Section: Introductionmentioning

confidence: 99%

Differential DNases are selectively used in neuronal apoptosis depending on the differentiation state

Shiokawa

Tanuma

2004

Cell Death Differ

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In this study, we investigate the roles of two apoptotic endonucleases, CAD and DNase c, in neuronal apoptosis. High expression of CAD, but not DNase c, is detected in proliferating N1E-115 neuroblastoma cells, and apoptotic DNA fragmentation induced by staurosporine under proliferating conditions is abolished by the expression of a caspaseresistant form of ICAD. After the induction of neuronal differentiation, CAD disappearance and the induction of DNase c occur simultaneously in N1E-115 cells. Apoptotic DNA fragmentation that occurs under differentiating conditions is suppressed by the downregulation of DNase c caused by its antisense RNA. The induction of DNase c is also observed during neuronal differentiation of PC12 cells, and apoptotic DNA fragmentation induced by NGF deprivation is inhibited by the antisense-mediated downregulation of DNase c. These observations suggest that DNA fragmentation in neuronal apoptosis is catalyzed by either CAD or DNase c depending on the differentiation state. Furthermore, DNase c is suggested to be involved in naturally occurring apoptosis in developing nervous systems.

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“…DNase II degrades DNA of apoptotic cells in lysosomes after phagocytes engulf them 16 . To examine the role of Tim4 in the engulfment of apoptotic cells, a fibroblast cell line expressing Tim4 was established with NIH3T3 expressing DNase II 10 (NIH3T3/DNase II/Tim4) ( Supplementary Fig.…”

mentioning

confidence: 99%

Identification of Tim4 as a phosphatidylserine receptor

Miyanishi

Tada

Koike

et al. 2007

Nature

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1,006

903

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In programmed cell death, a large number of cells undergo apoptosis, and are engulfed by macrophages to avoid the release of noxious materials from the dying cells 1,2 . In definitive erythropoiesis, nuclei are expelled from erythroid precursor cells and are engulfed by macrophages. Phosphatidylserine is exposed on the surface of apoptotic cells 3 and on the nuclei expelled from erythroid precursor cells 4 ; it works as an 'eat me' signal for phagocytes 5,6 . Phosphatidylserine is also expressed on the surface of exosomes involved in intercellular signalling 7 . Here we established a library of hamster monoclonal antibodies against mouse peritoneal macrophages, and found an antibody that strongly inhibited the phosphatidylserine-dependent engulfment of apoptotic cells. The antigen recognized by the antibody was identified by expression cloning as a type I transmembrane protein called Tim4 (T-cell immunoglobulin-and mucin-domain-containing molecule; also known as Timd4) 8 . Tim4 was expressed in Mac1 1 cells in various mouse tissues, including spleen, lymph nodes and fetal liver. Tim4 bound apoptotic cells by recognizing phosphatidylserine via its immunoglobulin domain. The expression of Tim4 in fibroblasts enhanced their ability to engulf apoptotic cells. When the anti-Tim4 monoclonal antibody was administered into mice, the engulfment of apoptotic cells by thymic macrophages was significantly blocked, and the mice developed autoantibodies. Among the other Tim family members, Tim1, but neither Tim2 nor Tim3, specifically bound phosphatidylserine. Tim1-or Tim4-expressing Ba/F3 B cells were bound by exosomes via phosphatidylserine, and exosomes stimulated the interaction between Tim1 and Tim4. These results indicate that Tim4 and Tim1 are phosphatidylserine receptors for the engulfment of apoptotic cells, and may also be involved in intercellular signalling in which exosomes are involved.Caspase-activated DNase (CAD)-deficient cells do not undergo apoptotic DNA fragmentation, but their DNA is degraded in phagocytes after they are engulfed 9 . We used this knowledge to assay the

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Impaired thymic development in mouse embryos deficient in apoptotic DNA degradation

Cited by 211 publications

References 50 publications

TAK1–JNK Axis Mediates Survival Signal through Mcl1 Stabilization in Activated T Cells

TAK1–JNK Axis Mediates Survival Signal through Mcl1 Stabilization in Activated T Cells

Differential DNases are selectively used in neuronal apoptosis depending on the differentiation state

Identification of Tim4 as a phosphatidylserine receptor

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