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3 0 0 0 OA デスレセプターを介するアポトーシス誘導に重要な新規分子DELEの同定とその機能解析

著者: 原田種展
巻号頁・発行日: 2010-09-24

Apoptosis is known as a form of programmed cell death, essential for the organogenesis of individuals, maintenance of the immune system, and elimination of injured cells and tumor cells. In cases when the regulatory mechanism of apoptosis becomes imbalanced, it induces severe diseases; for example, tumor development, breakdown of the immune system or neurodegeneration. Members of the death receptor (DR) family including tumor necrosis factor (TNF) receptor type1, Fas, DR3, TNF-related apoptosis inducing ligand receptors (TRAILR1/DR4 and TRAILR2/DR5) and DR6 are responsible to transduce apoptosis signal. These receptors are important for the regulation of many physiological and pathological events related to several human diseases. DR member family molecules induce apoptosis by the trimerization and aggregation of DR molecules on the plasma membrane. This receptor aggregation leads to recruitment of several subcellular proteins such as Fas-associated death domain protein (FADD) to the cytoplasmic domain of these receptors. The recruitment of FADD to DR is mediated through each death domain (DD) of DR to induce activation of caspases, cysteine proteases resulting in apoptosis induction. Death associated protein 3 (DAP3) is a GTP binding protein originally identified as a molecule which is responsible for activating interferon -induced apoptosis, and it has been reported that DAP3 is also important as a signal transducer for apoptosis induced by DR stimulation. In TRAIL induced apoptosis, DAP3 binds to TRAIL receptors, DR4 and DR5, and forms a complex with caspase-8 through FADD to activate caspase-8 depending on the stimulation of TRAIL. Thus, DAP3 is functional in cytoplasm for activation of TRAIL-mediated signaling pathway immediately downstream of DR4 and DR5. On the other hand, DAP3 is also observed abundantly in mitochondria, and the deletion mutant of DAP3 which lacks N-terminal region containing mitochondrial localization signal is not able to activate an apoptosis induced by the stimulation of FasL and TNF-. These observations suggest that the mitochondrial localized DAP3 is also responsible for induction of apoptosis. However, molecular mechanisms of mitochondrial DAP3 for induction of apoptosis are poorly understood. From this point of view, initially, the mitochondrial localized proteins were selected by using the prediction program of subcellular localization (PSORT II; http://psort.ims.u-tokyo.ac.jp/) from positive clones obtained by yeast two-hybrid screening, previously performed in our laboratory to identify DAP3-binding proteins. The results showed that the subcellular localization of one of the positive clones which encoded a functionally unknown protein was predicted to be localized in mitochondria. Consequently, focused on this clone designated as DELE (death ligand signal enhancer), the molecular functions of DELE were analyzed. The DELE protein is a 55 kDa protein consists of 515 amino acids, and found to contain a mitochondrial targeting sequence at the N-terminus, two tetratrico peptide repeat (TPR) motifs. In this study, the molecular functions of DELE on the apoptosis induced by the stimulation of TNF-, FasL and TRAIL were characterized. The co-immunoprecipitation analysis revealed that DELE actually binds to DAP3 in mammalian cells. The subcellular localization of DELE was analyzed by confocal laser scanning microscopy. The result shows that the subcellular localization of DELE is mainly observed in mitochondria, as was predicted by the analysis using PSORT II. The A549 cell lines in which the DELE gene is stably expressed were found to become susceptible to the apoptosis induction by the stimulation of TNF-, anti-Fas, and TRAIL. In addition, knockdown of DELE gene expression by siRNA treatment significantly protected the HeLa cells from the apoptosis induction by the stimulation of these cytokines. Moreover, activation of caspase-3, -8, and caspase-9 by these stimulations was significantly suppressed by the knockdown of DELE gene expression. In conclusion, this study demonstrated that the newly identified DELE regulates the death receptor-mediated apoptosis through the regulation of caspase activity.

2014-01-13 14:26:40
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http://hdl.handle.net/2115/43931

3 0 0 0 OA 「マルクス派最適成長論」の社会観・人間観 : 人間,自然,生産の関係と土台・上部構造論についての試論 (特集マルクス派最適成長論の展開と周辺問題)

著者: 大西広
出版者: 京都大学経済学会
雑誌: 經濟論叢 (ISSN:00130273)
巻号頁・発行日: vol.184, no.4, pp.3-25, 2010-10

3 0 0 0 OA 脳神経科学のメタ倫理学的含意 : 道徳判断と動機づけとの関係について

著者: 樫則章
出版者: Journal of medicine, life and ethics, society
雑誌: 医療・生命と倫理・社会 (ISSN:1348303X)
巻号頁・発行日: vol.11, pp.1-16, 2012-03-20

3 0 0 0 OA 「他者」概念の誕生 : 江藤淳の『夏目漱石』について

著者: 安天
出版者: 東京大学大学院総合文化研究科言語情報科学専攻
雑誌: 言語情報科学 (ISSN:13478931)
巻号頁・発行日: vol.10, pp.143-159, 2012-03-01

日本の批評における「他者」概念は、江藤淳の『夏目漱石』でその誕生を目撃することができる。本稿の目的は『夏目漱石』の論理構造の解明を通して -- (1)テクストのなかで「他者」概念が同書の他の主な概念とどのような関係を結んでおり、全体的な関係の網目のなかでどこに位置づけられているのかをあらわにすること。(2)テクストにおける論理展開に注目し、その展開から江藤の思考に見られる特徴を浮き彫りにすること -- この二点である。結論として、江藤は人の価値観を形づくり、世界を眺める視点を構成していく観念として「近代」「小説」「士君子的知識人」「自然」などを取り上げ、これらを「現実」を覆い隠し、「現実」を不可視にする虚構、言い換えれば認識を構成的に制限する知的装置として捉える一方、これらを取り除いた末にたどり着いた「現実」の地平において現れた不透明で、輪郭も定まらず、理解を拒む他人を、「他者」という言葉で概念化した -- という読解を提示する。

http://hdl.handle.net/2261/52664

3 0 0 0 OA 陰茎欠損症の1例

著者: 中井川昇寺島和光安達昌功立花克彦
出版者: 泌尿器科紀要刊行会
雑誌: 泌尿器科紀要 (ISSN:00181994)
巻号頁・発行日: vol.42, no.9, pp.695-697, 1996-09

生後0日目入院,男.在胎37週1日,後頭位自然分娩で,生下時2,300gであったが陰茎欠損に気付いて即日転科入院した.陰茎は根部から欠損して陰起もみられないが,陰嚢は2分陰嚢状で,腹部超音波で陰嚢内に正常精嚢があり,核型46XY.膀胱尿道造影で膀胱は正常であったが右膀胱尿管逆流IIを認めた.後部尿道,外尿道括約筋部は正常.女性内性器を認めなかった.両親と協議の末,2ヵ月後に両側精巣摘除,陰嚢切除を施行し,女児として養育することとした.陰茎欠損症の報告は日本で本例を含め7例と稀である.男として成長するより,女児として養育する方が社会的,心理的負担は少いと思われ,将来腟形成行を行う予定である