Nucling Recruits Apaf-1/Pro-caspase-9 Complex for the Induction of Stress-induced Apoptosis

Sakai, Takashi; Liu, Li; Teng, Xichuan; Mukai-Sakai, Rika; Shimada, Hidenori; Kaji, Ryuji; Mitani, Tomohiko; Matsumoto, Machiko; Toida, Kazunori; Ishimura, Kazunori; Shishido, Yuji; Mak, Tak W.; Fukui, Kiyoshi

doi:10.1074/jbc.m402902200

Cited by 51 publications

(57 citation statements)

References 34 publications

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“…Nucling, a protein of unknown function that is upregulated in cardiac muscle differentiation, has been proposed to act as a carrier for Apaf-1 nuclear uptake, since NuclingÀ/À MEFs do not show Apaf-1 relocalisation to the nucleus after UV irradiation. 30 These cells are also resistant to UV-induced cell death, suggesting that Apaf-1 might exert a proapoptotic function in the nucleus, at least in some apoptosis model systems.…”

Section: Apaf-1mentioning

confidence: 99%

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Nucleocytoplasmic transport in apoptosis

Ferrando‐May

2005

Cell Death Differ

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The apoptotic demolition of the nucleus is accomplished by diverse proapoptotic factors, most of which are activated in the cytoplasm and gain access to the nucleoplasm during the cell death process. The nucleus is also the main target for genotoxic insult, a potent apoptotic trigger. Signals generated in the nucleus by DNA damage have to propagate to all cellular compartments to ensure the coordinated execution of cell demise. The nucleocytoplasmic shuttling of signalling and execution factors is thus an integral part of the apoptotic programme. Several proteins implicated in apoptotic cell death have been shown to migrate in and out of the nucleus following apoptosis induction. This review summarises the current knowledge on nucleocytoplasmic trafficking of apoptosis-relevant proteins. The effects of apoptosis induction on the nucleocytoplasmic transport machinery are also discussed. Finally, a potential role of nuclear transport as a critical control point of the apoptotic signal cascade is proposed.

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Section: Apaf-1mentioning

confidence: 99%

“…29 Recent data, however, suggest that Apaf-1 might migrate to the nucleus also in mammalian cells during stress-induced apoptosis (e.g. Sakai et al 30 ). Nuclear translocation of Apaf-1 seems to be an early event preceding mitochondrial cytochrome C release.…”

Section: Apaf-1mentioning

confidence: 99%

Nucleocytoplasmic transport in apoptosis

Ferrando‐May

2005

Cell Death Differ

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“…Animal experiments and tissue preparation WT and Nucling-KO mice were prepared as described (14,15). Age-matched male mice between 8 and 12 weeks old were used for all experiments.…”

Section: Methodsmentioning

confidence: 99%

“…In addition, we have also reported that Nucling mediates apoptosis by inhibiting the expression of galectin-3 (16), an anti-apoptotic factor, through interference with NF-kB signalling pathway (17). Nucling is also associated with the apoptosome pathway by recruiting the Apaf-1/procaspase-9 complex following cytotoxic stress (14). However, Nucling-KO mice did not show any developmental abnormalities common to Apaf-1-or caspase-deficient mice because of the defect in apoptosis.…”

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confidence: 99%

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Nucling, a novel protein associated with NF-κB, regulates endotoxin-induced apoptosis in vivo

Kim

Sakai²,

Dang³

et al. 2012

The Journal of Biochemistry

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Nucling is a proapoptotic protein that regulates the apoptosome and nuclear factor-kappa B (NF-iB) signalling pathways. Strong stimuli, such as Gramnegative bacterial lipopolysaccharide (LPS), induce the simultaneous secretion of cytokines following the activation of NF-iB. Proinflammatory cytokines can induce liver damage through several mechanisms such as increases in oxidative stress and apoptotic reactions leading to tissue necrosis. Herein, we show that Nucling-knockout (KO) mice are resistant to LPS that consistently caused mortality in wild-type (WT) counterparts. Although serum levels of cytokines such as tumour necrosis factor (TNF)-a, interleukin (IL)-1b and IL-6 did not differ significantly between WT and Nucling-KO mice after the LPS challenge, hepatocytes of Nucling-KO mice were refractory to LPS-or TNF-a-induced cell death. These results were consistent with the decreased expression of proapoptotic proteins including apoptosis-inducing factor and cleaved form of poly (ADP-ribose) polymerase and terminal deoxynucleotidyl transferase dUTP nick end-labelling positive cells in the liver of Nucling-KO mice after the administration of a lethal dose of LPS. Moreover, the upregulation of NF-iB-regulated anti-apoptotic molecules including cellular inhibitor of apoptosis (cIAP) 1 and cIAP2 was observed in the liver of Nucling-KO mice after LPS treatment. These findings indicate that the Nucling deficiency leads to resistance to apoptosis in liver. We propose that Nucling is important for the induction of apoptosis in cells damaged by cytotoxic stressors through the NF-iB signalling pathway.

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Vascular endothelial growth factor receptor‐1 in human cancer

Schwartz

Rowinsky

Youssoufian

et al. 2010

Cancer

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The human vascular endothelial growth factor receptor-1 (VEGFR-1, or Flt-1) is widely expressed in normal and pathologic tissue and contributes to the pathogenesis of both neoplastic and inflammatory diseases. In human cancer, VEGFR-1 mediated signaling is responsible for both direct tumor activation and angiogenesis. VEGFR-1 mediated activation of nonmalignant supporting cells, particularly stromal, dendritic, hematopoietic cells, and macrophages, is also likely important for cancer pathogenesis. VEGFR-1 is also hypothesized to enable the development of cancer metastases by means of activation and premetastatic localization in distant organs of bone marrow-derived hematopoietic progenitor cells, which express VEGFR-1. IMC-18F1 is a fully human IgG 1 antibody that binds to VEGFR-1 and has been associated with the inhibition of cancer growth in multiple in vitro and human tumor xenograft models. The preliminary results of phase 1 investigations have also indicated a favorable safety profile for IMC-18F1 at doses that confer antibody concentrations that are associated with relevant antitumor activity in preclinical models. Cancer 2010;116(4 suppl):1027-32.

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Nucling Recruits Apaf-1/Pro-caspase-9 Complex for the Induction of Stress-induced Apoptosis

Cited by 51 publications

References 34 publications

Nucleocytoplasmic transport in apoptosis

Nucleocytoplasmic transport in apoptosis

Nucling, a novel protein associated with NF-κB, regulates endotoxin-induced apoptosis in vivo

Vascular endothelial growth factor receptor‐1 in human cancer

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