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Downstream of Akt: FoxO3 and m TOR in the regulation ofautophagy in skeltal muscle

AUTOPHAGY 2008年第4期4卷 524-526页

作者： Mammucari, Cristina Schiaffino, Stefano Sandri, Marco Venetian Inst Mol Med I-35129 Padua Italy Dulbecco Telethon Inst Padua Italy Univ Padua Dept Biomed Sci Padua Italy CNR Inst Neurosci Padua Italy

The balance between synthesis and degradation of intracellular components determines the overall muscle fiber size. Muscle atrophy occurs when the degradation rate is higher than the synthesis rate, for example during disuse, fasting or systemic diseases such as diabetes, cancer and renal failure. The two main catabolic systems that are activated during atrophy are the ubiquitin-proteasome and the autophagy-lysosome pathways. FoxO3 transcription factor causes marked atrophy in adult skeletal muscle and induces the muscle-specific ubiquitin ligase Atrogin-1/ MAFbx.(1) In addition, we recently reported that FoxO3 is necessary and sufficient for the induction of autophagy in skeletal muscle.(2) Transcription of autophagy related genes, such as LC3B and bnip3, is activated during fasting and is mediated by FoxO3. In particular, bnip3 induces autophagosome formation and is responsible for the induction of autophagy by FoxO3. Surprisingly, rapamycin is not able to induce autophagy in skeletal muscle in vivo, indicating that the Akt-FoxO axis, rather than the Akt-mTOR pathway, is involved in this process. Here we discuss the major implications of our recent work.

关键词： skeletal muscle FoxO atrophy LC3B bnip3 mTOR rapamycin muscle wasting

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A Dialogue between the Hypoxia-Inducible Factor and the Tumor Microenvironment

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CANCER MICROENVIRONMENT 2008年第1期1卷 53-68页

作者： Dayan, Frederic Mazure, Nathalie M. Brahimi-Horn, M. Christiane Pouyssegur, Jacques Univ Nice Inst Signaling Dev Biol & Canc Res CNRS UMR 6543Ctr Lacassagne 33 Ave Valombrose F-06189 Nice France

The hypoxia-inducible factor is the key protein responsible for the cellular adaptation to low oxygen tension. This transcription factor becomes activated as a result of a drop in the partial pressure of oxygen, to hypoxic levels below 5% oxygen, and targets a panel of genes involved in maintenance of oxygen homeostasis. Hypoxia is a common characteristic of the microenvironment of solid tumors and, through activation of the hypoxia-inducible factor, is at the center of the growth dynamics of tumor cells. Not only does the microenvironment impact on the hypoxia-inducible factor but this factor impacts on microenvironmental features, such as pH, nutrient availability, metabolism and the extracellular matrix. In this review we discuss the influence the tumor environment has on the hypoxia-inducible factor and outline the role of this factor as a modulator of the microenvironment and as a powerful actor in tumor remodeling. From a fundamental research point of view the hypoxia-inducible factor is at the center of a signaling pathway that must be deciphered to fully understand the dynamics of the tumor microenvironment. From a translational and pharmacological research point of view the hypoxia-inducible factor and its induced downstream gene products may provide information on patient prognosis and offer promising targets that open perspectives for novel "anti-microenvironment" directed therapies.

关键词： Angiogenesis Autophagy bnip3 Cancer Carbonic anhydrase Factor inhibiting HIF-1 Hypoxia Hypoxia-inducible factor Oxygen-sensor Tumor metabolism pH regulation

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bnip3基因及其与肿瘤的关系

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国际病理科学与临床杂志 2006年第4期26卷 298-301页

作者：谢晋予郑长黎中南大学湘雅医学院病理学系长沙410078

bnip3是bc l-2家族中BH3-on ly亚家族的成员,具有BH3结构域和跨膜区,属于促凋亡蛋白。bnip3通过促进线粒体通透性转运孔开放和线粒体的损伤诱导凋亡,其表达受缺氧和其他因素的影响。近年研究发现bnip3的表达异常和许多肿瘤的进展及耐药... 详细信息

bnip3是bc l-2家族中BH3-on ly亚家族的成员,具有BH3结构域和跨膜区,属于促凋亡蛋白。bnip3通过促进线粒体通透性转运孔开放和线粒体的损伤诱导凋亡,其表达受缺氧和其他因素的影响。近年研究发现bnip3的表达异常和许多肿瘤的进展及耐药性有关。

关键词： bnip3 凋亡肿瘤

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先兆子痫、胎儿宫内发育受限及HELLP综合征患者胎盘组织中细胞凋亡诱导因子bnip3及Nix的定位及表达

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世界核心医学期刊文摘（妇产科学分册） 2006年第2期2卷 16-17页

作者： Stepan H. Leo C. Purz S. 张剑萍 Department of Obstetrics and Gynecology University of Leipzig Philipp-Rosenthalstr. 55 04103 Leipzig Germany

Objective: bnip3 and its homologue Nix are pro-apoptotic factors of the Bcl-2-family and are expressed in malignant tumors. In vitro, this expression was shown to be mediated by hypoxia. Recently, it has been shown that placental hypoxia as well as apoptosis are pathogenetic factors for pregnancy-induced hypertensive diseases and intrauterine growth retardation (IUGR). The aim of the study was to analyze placental expression of bnip3 and Nix in pregnancies complicated by preeclampsia, hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome and IUGR. Material and methods: Placental tissue was sampled from 10 pregnancies each with preeclampsia, HELLP syndrome, IUGR and gestational age-matched controls. The placental expression of bnip3/Nix has been investigated with immunohistochemistry by the use of specific human bnip3/Nix antibodies. Results: In cytotrophoblastic cells, the bnip3 expression was strong in the control placentas, but only mediate in the placentas from pregnancies with preeclampsia, IUGR or HELLP syndrome. The intensity of the Nix staining showed a similar pattern. In the syncytiotrophoblast, there was a weak bnip3 staining observable in the control as well as IUGR samples, whereas bnip3 was undetectable in preeclamptic placentas or those with HELLP syndrome. For Nix, only in the preeclampsia a weak staining was detectable, whereas all other probes were negative. Conclusions: Our study shows for the first time that the proapoptotic proteins bnip3 and Nix are expressed in the human placenta. Pregnancies with placental dysfunction and hypertensive pregnancy disorders with different clinical manifestations are characterized by a significantly decreased expression of bnip3 and Nix. These results suggest that the hypothesis of generally increased placental apoptosis in pregnancy-induced hypertensive disorders caused by disturbed trophoblast invasion has to be partly reconsidered.

关键词： HELLP综合征胎儿宫内发育胎盘组织 bnip3 Nix 凋亡诱导因子先兆子痫肝酶升高合体

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脑缺血海马caspase非依赖性凋亡相关蛋白表达水平的改变

脑缺血海马caspase非依赖性凋亡相关蛋白表达水平的改变

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作者：行艳丽南方医科大学

学位级别：硕士

脑血管病发病率高,严重危害人类健康,是当今第三大死亡原因及首位致残原因。脑缺血/缺氧损伤所致的神经元大量死亡是导致中风后神经功能丧失的主要原因,而目前对缺血性脑损伤的机制仍未阐明,临床也无理想的治疗手段。脑中风可引起缺血... 详细信息

脑血管病发病率高,严重危害人类健康,是当今第三大死亡原因及首位致残原因。脑缺血/缺氧损伤所致的神经元大量死亡是导致中风后神经功能丧失的主要原因,而目前对缺血性脑损伤的机制仍未阐明,临床也无理想的治疗手段。脑中风可引起缺血中心区神经元的急性损伤,以及缺血半暗区神经元的继发性损伤,即迟发性神经元死亡。迟发性神经元死亡的发生机制主要为凋亡,凋亡是一种高度调节的程序性细胞死亡过程,以往的研究表明,caspase（天冬氨酸特异性半胱氨酸蛋白酶）依赖性机制在这一过程中起重要作用,但最近有越来越多的研究表明casepase非依赖性机制也参与了迟发性神经元死亡。虽然目前对caspase非依赖性细胞凋亡的调节机制尚不明确,但已经发现了一些与caspase非依赖性细胞凋亡相关的分子,如bnip3,AIF,EndoG,ARPP等。 bnip3（Bcl-2/adenovirus E1B-19K相互作用蛋白3）是一种促凋亡蛋白,属于Bcl-2家族促细胞凋亡亚家族中的BH3-only亚家族,研究表明bnip3参与了包括上皮细胞,心肌细胞,神经胶质细胞,神经元等多种细胞的死亡过程。内源性bnip3与线粒体疏松结合,当受到凋亡信号刺激时,bnip3靠它的跨膜结构域插入线粒体外膜,引起线粒体通透性转换孔（permeability transition pores,PTP）开放,线粒体膜内外电化学梯度降低,氧自由基产生增多,线粒体功能失调,进而导致细胞死亡。bnip3介导的细胞死亡不依赖于细胞色素C的释放以及Apaf-1,caspase的激活,以早期质膜以及线粒体膜损伤为特点。但bnip3是否参与大鼠全脑缺血/再灌注损伤中海马神经元的死亡以及引起细胞死亡的机制目前还不清楚。缺氧诱导因子-1（HIF-1）是目前唯一比较明确的调控bnip3表达水平的上游信号分子,但目前对于bnip3引起细胞死亡的下游分子机制还不清楚。AIF与EndoG是已知的线粒体功能障碍的下游分子,参与了caspase非依赖性细胞死亡通路。AIF和EndoG是存在于线粒体内外膜之间的凋亡相关蛋白。当细胞受到特定的凋亡诱导信号的刺激后,线粒体膜上的PTP打开,允许它们从线粒体释放到胞浆,并转位到核内进而引起DNA的大片段裂解,但AIF本身没有核酶的特性,它的DNA降解作用是通过其它核酶来实现的。EndoG很可能是AIF的相互作用分子。AIF和EndoG参与多种细胞的死亡通路,但其是否是bnip3诱导细胞死亡的下游分子目前尚不明确。我们首先观察了脑缺血/再灌注后海马bnip3表达水平的动态变化。采用改良的Pulsinelli四血管闭塞法制做大鼠全脑缺血模型,通过尼氏染色观察海马神经元的存活状况,与假手术组相比,缺血后7天的海马CA1区有大量神经细胞皱缩,胞核碎裂消失,结构不清,证明我们的模型确实引起海马神经元的死亡。通过Western Blot观察了bnip3在脑缺血/再灌注后不同时间点大鼠海马组织及其线粒体中的表达清况。在缺血/再灌注后不同时间点,假手术组于术后24小时麻醉大鼠,断头取脑,分离海马组织,提取全细胞及线粒体样品。全细胞样品的结果:发现bnip3单体（30KD）于缺血/再灌注后增加,差别有统计学意义(F（6,14）=5.330,P=0.005);缺血/再灌注后1小时组与假手术组相比增加2.26倍,差别有统计学意义（P＜0.05）;缺血/再灌注后2,6,12小时组增加量分别为假手术组的2.60,2.93,2.61倍,差别有统计学意义（P＜0.01）;bnip3双聚体（60KD）在缺血/再灌注后表达水平的改变无统计学差异(F（6,28）=0.028,P=0.942)。海马组织线粒体中没有观察到bnip3单体的表达,而bnip3双聚体在缺血/再灌注后增加,差别有统计学意义(F（6,28）=2.699,P=0.034)。仅缺血/再灌注后24小时组与假手术组相比差别有统计学意义（P＜0.05）。bnip3表达水平的改变提示它可能参与了大鼠脑缺血/再灌注后海马神经元的死亡。最后,通过Western Blot观察AIF和EndoG在脑缺血/再灌注后不同时间点的大鼠海马组织及其线粒体中的表达清况。结果发现在海马组织及其线粒体中,缺血/再灌注损伤后AIF蛋白水平改变均无统计学差异(F（6,21）=1.070,P=0.411;F（6,14）=1.089,P=0.415),而海马组织及其线粒体中的EndoG蛋白水平在缺血/再灌注后均增高,差别有统计学意义(F（6,5.333）=38.831,P=0.000;F（6,5.333）=27.050,P=0.001)。仅缺血/再灌注后24小时组与假手术组比较差别有统计学意义（P＜0.05）。这一结果与预期结果（EndoG核转位后

关键词：脑缺血海马线粒体 bnip3 AIF EndoG caspase非依赖性凋亡

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促凋亡线粒体蛋白bnip3在弥漫型星形细胞瘤组织中的表达及与肿瘤分级之间相关性的研究

促凋亡线粒体蛋白BNIP3在弥漫型星形细胞瘤组织中的表达及与肿瘤...

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中华医学会病理学分会2006年学术年会

作者：刘馨莲曾浩黄蕤陈铌王晓洁殷舞陈雪芹周桥四川大学华西医院病理研究室病理科四川大学华西医院病理研究室病理科四川大学华西医院病理研究室病理科四川大学华西医院病理研究室病理科四川大学华西医院病理研究室病理科四川大学华西医院病理研究室病理科四川大学华西医院病理研究室病理科四川大学华西医院病理研究室病理科

目的探讨Bcl-2家族促凋亡线粒体蛋白bnip3在弥漫型星形细胞瘤组织中的表达及与肿瘤分级之间相关性。方法采用免疫组织化学LsAB法检测9例弥漫性星形细胞瘤(WHO Ⅱ)、9例间变性星形细胞瘤(WHOⅢ)、11例多型性胶质母细胞瘤(WHOⅣ)组织中BN... 详细信息

目的探讨Bcl-2家族促凋亡线粒体蛋白bnip3在弥漫型星形细胞瘤组织中的表达及与肿瘤分级之间相关性。方法采用免疫组织化学LsAB法检测9例弥漫性星形细胞瘤(WHO Ⅱ)、9例间变性星形细胞瘤(WHOⅢ)、11例多型性胶质母细胞瘤(WHOⅣ)组织中bnip3的表达;采用RT-PCR、Western-Blot法检测7例正常脑组织、7例弥漫性星形细胞瘤、5例间变性星形细胞瘤、9例多型性胶质母细胞瘤中bnip3的表达,并对bnip3表达与弥漫型星形细胞瘤病理分级之间的相关性进行统计学分析。结果免疫组织化学LsAB法检测结果显示,bnip3在弥漫性星形细胞瘤(WHO Ⅱ)、间变性星形细胞瘤(WHO Ⅲ)和多型性胶质母细胞瘤(WHOⅣ)中的表达阳性率分别为33．3％(3／9)、33．3％(3／9)、100％ (11／11),统计分析结果显示,bnip3在WHOⅣ组织中的表达与在WHOⅡ和WHOⅢ的表达之间存在明显统计学差异(P<0．05),而其在WHOⅡ和WHOⅢ组织中的表达没有差异(P>0．05)。 RT-PCR结果显示bnip3在正常脑组织中低表达, 在弥漫型星形细胞瘤组织中表达水平明显上升, 且随着级别增高而增高。在7例正常脑组织和7 例弥漫性星形细胞瘤(WHO Ⅱ)中用Western-Blot 法未检测到bnip3蛋白的表达,在5例间变性星形细胞瘤(WHOⅢ)中有2例表达,9例多型性胶质母细胞瘤中均有bnip3蛋白的表达。结论 Bcl-2家族促凋亡线粒体蛋白bnip3在弥漫型星形细胞瘤组织中存在明显高表达,且其表达水平随着肿瘤级别增高而增高,是评估弥漫型星形细胞瘤预后的潜在因素之一。

关键词： bnip3 弥漫型星形细胞瘤分级

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bnip3 and signal-specific programmed death in the heart

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JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY 2005年第1期38卷 35-45页

作者： Webster, KA Graham, RM Bishopric, NH Univ Miami Med Ctr Dept Mol & Cellular Pharmacol Miami FL 33136 USA Univ Miami Med Ctr Vasc Biol Inst Miami FL 33101 USA Univ Miami Med Ctr Dept Med Miami FL 33136 USA Univ Miami Med Ctr Dept Pediat Miami FL 33136 USA

The BH3-only proteins, including bnip3, are members of the Bcl-2 family of cell death-regulating factors. Whereas proteins such as Bax and Bak play a central role in most forms of apoptosis, the BH3-only proteins appear to modulate apoptosis through cell type- and signal-specific pathways. This review will focus oil our studies of the specific role of bnip3 in cardiac myocyte apoptotic signaling during ischemia. We recently showed that hypoxia in the presence of high glucose leads to progressive acidosis of cardiac myocytes in culture. Cardiac myocytes are resistant to chronic hypoxia at neutral pH but undergo extensive death when the [pH](o) drops below 6.5. A micro-array analysis of 20,000 genes identified the pro-apoptotic Bcl-2 family member bnip3 as one of the most strongly upregulated of >100hypoxia-inducible genes in cardiac myocytes. bnip3 mRNA increased by 12-fold. and bnip3 protein by sixfold. during 24 h of hypoxia-bnip3 protein accumulation was further enhanced by acidosis. bnip3 was loosely bound to mitochondria under conditions of neutral hypoxia but became more tightly associated at acid pH, coincident with opening of the mitochondrial permeability transition pore (MPTP). Subsequent DNA fragmentation and cell death were not blocked by caspase inhibitors, but were inhibited by antisense bnip3 oligonucleotides and MPTP inhibitors, indicating that bnip3 activates ail atypical programmed death pathway with features of both apoptosis and necrosis. The sequential induction and activation of bnip3 by hypoxia and acidosis provide a molecular basis for the observation that chronic hypoxia at neutral pH does not promote apoptosis or activate caspases in neonatal cardiac myocytes. (C) 2004 Elsevier Ltd. All rights reserved.

关键词： cardiac myocyte heart apoptosis ischemia pH bnip3 mitochondria necrosi

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Uncoupling protein 2 modulates cell viability in adult rat cardiomyocytes

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AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY 2007年第1期293卷 H829-H835页

作者： Bodyak, Natalya Rigor, Debra L. Chen, Yee-Shiuan Han, Yuchi Bisping, Egbert Pu, William T. Kang, Peter M. Harvard Univ Beth Israel Deaconess Med Ctr Dept Med Div Cardiovasc Cambridge MA 02138 USA Childrens Hosp Dept Cardiol Boston MA 02115 USA

Uncoupling protein 2 (UCP2) is an inner mitochondrial membrane proton carrier that uncouples ATP synthesis. The aim of this study was to determine whether UCP2 plays a role in survival of adult rat cardiac myocytes. We first studied the effects of UCP2 overexpression in vitro. Overexpression of UCP2 in primary cardiomyocytes led to a significant decline in ATP level and the development of acidosis but had no observable effect on cell survival. When cardiomyocytes were challenged with hypoxia-reoxygenation, cells overexpressing UCP2 survived significantly less compared with control. This finding was associated with upregulation of proapoptotic protein Bcl-2 and 19-kDa interacting protein 3 (bnip3). Furthermore, UCP2 short interfering RNA prevented both the increase in cell death and bnip3 expression. To examine the in vivo role of UCP2 in the heart, we used the Dahl salt-sensitive rat heart-failure model. Northern blot analysis revealed that UCP2 mRNA level was significantly upregulated in rat heart failure along with bnip3 protein level. In conclusion, UCP2 increases sensitivity of adult rat cardiac myocytes to hypoxia-reoxygenation by way of ATP depletion and acidosis, which in turn causes accumulation of prodeath protein bnip3.

关键词： survival bnip3 ATP cell death Dahl salt-sensitive rat cell death

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Increased bnip3 and decreased mutant p53 in cisplatin-sensitive PDT-resistant HT29 cells

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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 2005年第2期331卷 648-657页

作者： Zacal, N Espiritu, M Singh, G Rainbow, AJ Juravinski Canc Ctr Hamilton ON Canada McMaster Univ Dept Biol Hamilton ON Canada McMaster Univ Dept Pathol & Mol Med Hamilton ON Canada

We have reported previously the isolation of three photodynamic therapy (PDT)-resistant human colon carcinoma HT29 cell lines that shorn increased expression of the Hsp27 and bnip3 protein and a decreased expression of the mutant p53 protein compared to parental HT29 cells. Since Mutant p53 and increased expression of Hsp27 liar c been associated with resistance to various chemotherapeutic agents. whereas bnip3 is a potent inducer of apoptosis, we were interested in determining whether these PDT-resistant cells were cross-resistant to other cytotoxic agents. We report here that the PDT-resistant HT29 cell lines showed a significant increase in cisplatin sensitivity and an increase in both Spontaneous and cisplatin-induced apoptosis compared to parental HT29 cells. In addition. the cisplatin sensitivity of the PDT-resistant HT29 variants and several other clonal variants of HT29 cells correlated with increased bnip3 and decreased mutant p53 protein levels. but not Hsp27 protein levels, (c) 2005 Elsevicr Inc. All rights reserved.

关键词： PDT resistance cisplatin sensitvity bnip3 p53 Hsp27 HT29 cells apoptosis

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Arsenic trioxide induces autophagic cell death in malignant glioma cells by upregulation of mitochondrial cell death protein bnip3

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ONCOGENE 2005年第6期24卷 980-991页

作者： Kanzawa, T Zhang, L Xiao, LC Germano, IM Kondo, Y Kondo, S Univ Texas MD Anderson Canc Ctr Dept Neurosurg Unit 64 Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr Dept Biostat Houston TX 77030 USA Mt Sinai Sch Med Dept Neurosurg New York NY 10510 USA

Arsenic trioxide (As2O3) has shown considerable efficacy in treating hematological malignancies with induction of programmed cell death (PCD) type I, apoptosis. However, the mechanisms underlying the antitumor effect of As2O3 on solid tumors are poorly defined. Previously, we reported that As2O3 induced autophagic cell death (PCD type II) but not apoptosis in human malignant glioma cell lines. The purpose of this study was to elucidate the molecular pathway leading to autophagic cell death. In this study, we demonstrated that the cell death was accompanied by involvement of autophagy-specific marker, microtubule-associated protein light chain 3 (LC3), and damage of mitochondrial membrane integrity, but not by caspase activation. Analysis by cDNA microarray, RT-PCR, and Western blot showed that cell death members of Bcl-2 family, Bcl-2/adenovirus E1B 19-kDa- interacting protein 3 (bnip3) and its homologue bnip3-like (bnip3L), were upregulated in As2O3-induced autophagic cell death. Exogenous expression of bnip3, but not bnip3L, induced autophagic cell death in malignant glioma cells without As2O3 treatment. When upregulation of bnip3 induced by As2O3 was suppressed by a dominant-negative effect of the transmembrane-deleted bnip3 (bnip3DTM), autophagic cell death was inhibited. In contrast, bnip3 transfection augmented As2O3-induced autophagic cell death. These results suggest that bnip3 plays a central role in As2O3-induced autophagic cell death in malignant glioma cells. This study adds a new concept to characterize the pathways by which As2O3 acts to induce autophagic cell death in malignant glioma cells.

关键词： arsenic trioxide autophagy bnip3 glioma LC3

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