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Thymidine phosphorylase inhibits the expression of proapoptotic protein bnip3

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 2008年第2期370卷 220-224页

作者： Ikeda, Ryuji Tajitsu, Yusuke Iwashita, Ken-ichi Che, Xiao-Fang Yoshida, Kenichi Ushiyama, Mina Furukawa, Tatsuhiko Komatsu, Masaharu Yamaguchi, Tatsuya Shibayama, Yoshihiko Yamamoto, Masatatsu Zhao, Hong-Ye Arima, Junko Takeda, Yasuo Akiyama, Shin-ichi Yamadaa, Katsushi Kagoshima Univ Grad Sch Med & Dent Sci Dept Mol Oncol Kagoshima 8908520 Japan Kagoshima Univ Grad Sch Med & Dent Sci Dept Clin Pharm & Pharmacol Kagoshima 8908520 Japan Kagoshima Univ Grad Sch Med & Dent Sci Dept Environm Med Kagoshima 8908520 Japan Meiji Univ Sch Agr Dept Life Sci Kanagawa 2148571 Japan

An angiogenic factor, thymidine phosphorylase (TP), confers resistance to apoptosis induced by hypoxia. We investigated the molecular basis for the suppressive effect of TP on hypoxia-induced apoptosis using Jurkat cells transfected with TP cDNA, Jurkat/TP, and a mock transfectant, Jurkat/CV. TP and 2-deoxy-D-ribose, a degradation product of thymidine generated by TP enzymatic activity, suppressed hypoxia-induced apoptosis. They also inhibited the upregulation of hypoxia-inducible factor (HIF) 1 alpha and the proapoptotic factor, bnip3, and caspase 3 activation induced by hypoxia. Introduction of siRNA against bnip3 in Jurkat cells decreased the proportion of apoptotic cells under hypoxic condition. These findings suggest that the suppression of bnip3 expression by TP prevents, at least in part, hypoxia-induced apoptosis. Expression levels of TP are elevated in many malignant solid tumors and thus 2-deoxy-D-ribose generated by TP in these tumors might play an important role in tumor progression by preventing hypoxia-induced apoptosis. (C) 2008 Elsevier Inc. All rights reserved.

关键词： thymidine phosphorylase 2-deoxy-D-ribose apoptosis hypoxia-inducible factor-1 alpha bnip3 hypoxia

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Expression of bnip3 correlates with hypoxia-inducible factor (HIF)-1α, HIF-2α and the androgen receptor in prostate cancer and is regulated directly by hypoxia but not androgens in cell lines

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PROSTATE 2008年第3期68卷 336-343页

作者： Shaida, Nadeem Launchbury, Rosalind Boddy, Jane L. Jones, Catherine Campo, Leticia Turley, Helen Kanga, Suresh Banham, Alison H. Malone, Peter R. Harris, Adrian L. Fox, Stephen B. Peter MacCallum Canc Ctr Melbourne Vic 3002 Australia Royal Berkshire Hosp Harold Hopkins Dept Urol Reading Berks England Univ Oxford John Radcliffe Hosp Nuffield Dept Clin Lab Sci Oxford OX1 2JD England Univ Oxford John Radcliffe Hosp Weatherall Inst Mol Med Mol Oncol Lab Oxford OX1 2JD England

BACKGROUND. bnip3 is a hypoxia-induced protein involved in cell death and survival but its role in human tumors is unclear. This study investigated the role of bnip3 in prostate cancer. METHODS. The expression of bnip3, the androgen receptor (AR), hypoxia inducible factor (HIF)-1 alpha, HIF-2 alpha and the hypoxia regulated gene GLUT1 were assessed in tissue microarrays constructed from 149 radical prostatectomy specimens. Statistics compared expression of these factors between each other, conventional clinicopathological parameters and PSA recurrence. Since an association between bnip3 and AR and the HIFs was observed, the influence of hypoxia, clihydrotestosterone and the AR blocker, Casodex, was also investigated in prostate cell lines. RESULTS. bnip3 was expressed in the nucleus and cytoplasm. Eight of 149 (5.5%) tumors showed no expression, 44/149 (29.5%) cases showed exclusively cytoplasmic expression, 17/149 (11.5%) cases showed exclusively nuclear expression and 80/149 (53.5%) cases showed both cytoplasmic and nuclear expression. There was a significant correlation between cytoplasmic bnip3 expression and Gleason score (P = 0.005), age (P = 0.02), AR (P = 0.001), and GLUT1 (P = 0.006). There was a significant correlation between nuclear bnip3 expression and HIF-1 alpha expression (P = 0.006) and HIF-2 alpha expression (P = 0.013) but no correlation between bnip3 and pre-operative PSA, tumor volume, margin positivity or capsular invasion (all P > 0.05). There was an increase in bnip3 expression under conditions of hypoxia (0-1% 02) but not with dihydrotestosterone stimulation or with Casodex treatment. CONCLUSIONS. These findings suggest that bnip3 is directly regulated by hypoxia but that there may be a hormonal independent mechanism coordinating the expression of bnip3 in prostate tumors.

关键词： prostate bnip3 hypoxia autophagy androgen receptor

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Hypoxia signals autophagy in tumor cells via AMPK activity, independent of HIF-1, bnip3, and bnip3L

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CELL DEATH AND DIFFERENTIATION 2008年第10期15卷 1572-1581页

作者： Papandreou, I. Lim, A. L. Laderoute, K. Denko, N. C. Stanford Univ Sch Med Dept Radiat Oncol Div Radiat & Canc Biol Stanford CA 94305 USA SRI Int Biosci Div Menlo Pk CA 94025 USA

Macroautophagy (called autophagy hereafter) is a catabolic process activated by various types of stress, most notably by nutrient deprivation. The autophagic degradation of intracellular macromolecules provides metabolic support for the cell;however, this physiological process can also initiate a form of cell death (type 2 programmed cell death). Here we report that oxygen deprivation can activate the autophagic pathway in human cancer cell lines. We observed that hypoxia induced distinct cellular changes characteristic of autophagy such as an increase in cytoplasmic acidic vesicles, and processing and cellular localization of microtubule-associated protein-1 light chain 3. Oxygen deprivation-induced autophagy did not require nutrient deprivation, hypoxia-inducible factor-1 (HIF-1) activity, or expression of the HIF-1 target gene bnip3 (Bcl-2 adenovirus E1a nineteen kilodalton interacting protein 3) or bnip3L (bnip3 like protein). Hypoxia-induced autophagy involved the activity of 5'-AMP-activated protein kinase (AMPK). Finally, we determined that cells lacking the autophagy gene ATG5 were unable to activate the autophagic machinery in hypoxia, had decreased oxygen consumption and increased glucose uptake under hypoxia, had increased survival in hypoxic environments, and exhibited accelerated growth as xenografted tumors. Together, these findings suggest that the autophagic degradation of cellular macromolecules contributes to the energetic balance governed by AMPK, and that suppression of autophagy in transformed cells can increase both resistance to hypoxic stress and tumorigenicity.

关键词： hypoxia AMPK bnip3 respiration programmed cell death

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抗阻、有氧运动对自然衰老小鼠骨骼肌Sarcopenia关联的自噬系统相关基因表达的影响

抗阻、有氧运动对自然衰老小鼠骨骼肌Sarcopenia关联的自噬系统相...

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作者：赵永军华东师范大学

学位级别：硕士

随着中国改革开放的深入与经济建设的突飞猛进,人们的物质生活水平有了质的飞跃,但随之而发生的是生活方式及饮食习惯的改变,如身体活动减少、摄入过多脂类和糖类、吸烟、酗酒等,这就造成许多“现代文明病”的发生,即人们由于体力活动减... 详细信息

随着中国改革开放的深入与经济建设的突飞猛进,人们的物质生活水平有了质的飞跃,但随之而发生的是生活方式及饮食习惯的改变,如身体活动减少、摄入过多脂类和糖类、吸烟、酗酒等,这就造成许多“现代文明病”的发生,即人们由于体力活动减少,热量摄入增多,导致机体热量处于正平衡状态,体脂堆积增加,骨骼肌质量减少等。这些病症一旦出现,对机体的影响就会持续下去,特别是骨骼肌中葡萄糖代谢紊乱造成胰岛素抵抗(IR),会诱导特定信号通路激活,导致骨骼肌发生一系列退行性变化,Sarcopenia就是其中威胁老年人骨骼肌健康的危险病征之- Sarcopenia是一种在老年人中常见的以骨骼肌质量(数量和体积)和力量随增龄下降为特征的病征,其中以Ⅱ型肌纤维为主。它可致使机体功能降低、劳动能力丧失甚至于生活不能自理,虽然这种病征在老年人中很常见,并且严重威胁老年人的健康及生活质量,但就目前来说,其发生机制还不是很清楚。其中蛋白质代谢失衡是重要原因之一,研究显示,随着年龄增加骨骼肌蛋白质合成能力下降而其降解速度却增快,这就造成由蛋白质为主构成的骨骼肌体积的下降,继而发生肌力下降。另一重要机制就是细胞凋亡的发生可能导致了骨骼肌细胞数量的减少,从而造成骨骼肌萎缩。其中线粒体介导的caspase依赖性细胞凋亡被认为是Sarcopenia发生的主要因素。但近年来发现Ⅱ型程序性细胞死亡---自噬性程序性细胞死亡(Autophagy)可能在Sarcopenia的发生发展中也起到关键作用。Autophagy作为细胞内重要的蛋白质降解途径,其对Sarcopenia不仅限于可直接发生细胞凋亡从而减少骨骼肌纤维数量,还在于它可调控骨骼肌内蛋白质代谢平衡。Autophagy的失活或者过度激活都将影响细胞内蛋白质含量,并将激发一些列连锁反应。所以无论是细胞凋亡通路还是蛋白质代谢失衡,Autophagy对骨骼肌的调节作用将非常关键,这可能为预防和治疗Sarcopenia提供新的启示。众所周知,运动特别是抗阻运动可以促进骨骼肌生理性肥大,这就为预防和缓解Sarcopenia提供了思路,研究也显示抗阻运动可在一定程度范围内延缓Sarcopenia的发生,但不同时限的抗阻训练可能造成不同的影响。另外,抗阻运动预防Sarcopenia的作用机制还不是很清楚,虽然很多学者从不同角度进行了研究与探讨,但尚未发现有研究者从自体吞噬的角度说明探讨Sarcopenia的发生机制,及运动延缓Sarcopenia的作用机制。本文通过对C57BL/6自然衰老小鼠进行终身跑台、爬梯运动训练,利用Q-PCR的生物学方法检测Autophagy相关基因LC3、Beclinl、LAMP-2和bnip3的表达,探讨Sarcopenia发生发展中Autophagy的变化及运动训练对自体吞噬相关基因表达的影响,试图从自体吞噬的角度理解和解释Sarcopenia的发生机制和运动预防Sarcopenia的作用机理。方法：54只C57BL/6小鼠随机分为青年对照组(YC)、老年对照组(0C)、终身跑台组(LE)、终身爬梯组(LR)、老年跑台组(OE)、老年爬梯组(OR)六组,每组各9只,其中YC组为3月龄,其余各组自然生长至20月龄。LE组和LR组分别进行为期17个月的跑台和爬梯训练,OE组和OR组分别进行为期2个月的跑台和爬梯训练,跑台、爬梯训练每周3次。利用Q-PCR的生物学方法检测Autophagy相关基因LC3、Beclinl、LAMP-2和bnip3的表达,并根据实际适应情况调整运动量与强度。结果：1)C57BL/6自然衰老小鼠骨骼肌质量下降,出现严重Sarcopenia征状。2)与YC组比较,OC组小鼠LC3b、LAMP-2b和bnip3 mRNA表达量显著升高,LC3a、Beclinl和LAMP-2a mRNA的变化无显著性差异。3)与OC组相比,终身耐力训练可使LC3a显著升高；使LC3b、Beclin、LAMP-2a、LAMP-2b和bnip3 mRNA表达量显著降低。4)与OC组相比,终身抗阻训练可使LC3a、Beclinl、LAMP-2a mRNA表达量降低,但无显著性差异；使LC3b、bnip3 mRNA得表达量显著降低。5)与LE组相比,Beclinl、LAMP-2a、LAMP-2b表达量升高,且具有极显著性差异。结论：1)20月龄C57BL/6小鼠符合Sarcopenia研究标准,可作为研究Sarcopenia的模式动物。2)20月龄C57BL/6小鼠LC3b、LAMP-2b和bnip3 mRNA表达量显著升高,且LC3b/LC3a比值显著升高推测自体吞噬活性显著升高,可能造成细胞过度自噬造成蛋白质降解增加,出现骨骼肌质量减少,进而诱导产生Sarcopeniao 3)终身耐力运动可在小鼠青

关键词：骨骼肌衰减征自体吞噬 LC3 Beclin1 LAMP-2 bnip3 耐力运动抗阻运动

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Bortezomib blocks the catabolic process of autophagy via a cathepsin-dependent mechanism, affects endoplasmic reticulum stress and induces caspase-dependent cell death in antiestrogen-sensitive and resistant ER⁺ breast cancer cells

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AUTOPHAGY 2010年第1期6卷 19-35页

作者： Periyasamy-Thandavan, Sudharsan Jackson, William H. Samaddar, Julia S. Erickson, Brian Barrett, John R. Raney, Lauren Gopal, Elangovan Ganapathy, Vadivel Hill, William D. Bhalla, Kapil N. Schoenlein, Patricia V. Med Coll Georgia Dept Cellular Biol & Anat Augusta GA 30912 USA Med Coll Georgia Dept Biochem & Mol Biol Augusta GA 30912 USA Med Coll Georgia MCG Inst Canc Augusta GA 30912 USA

In recent studies, we and others showed that autophagy is critical to estrogen receptor positive (ER+) breast cancer cell survival and the development of antiestrogen resistance. Consequently, new approaches are warranted for targeting autophagy in breast cancer cells undergoing antiestrogen therapy. Because crosstalk has been demonstrated between the autophagy- and proteasome-mediated pathways of protein degradation, this study investigated how the proteasome inhibitor bortezomib affects autophagy and cell survival in antiestrogen-treated ER+ breast cancer cells. Bortezomib, at clinically achievable doses, induced a robust death response in ER+, antiestrogen-sensitive and antiestrogen-resistant breast cancer cells undergoing hormonal therapy. Cleavage of PARP and lamin A was detectable as a read-out of cell death, following bortezomib-induced mitochondrial dysfunction. Prior to induction of cell death, bortezomib-treated cells showed high levels of light chain 3 (LC3) and p62, two protein markers for autophagy. The accumulation of these proteins was due to bortezomib-mediated blockade of long-lived protein turnover during macroautophagy. This novel action of bortezomib was linked to its blockade of cathepsin-L activity, which is required for autolysosomal-mediated protein turnover in ER+ breast cancer cells. Further, bortezomib-treated breast cancer cells showed induction of the unfolded protein response, with upregulation of CHOP and GRP78. Bortezomib also induced high levels of the pro-apoptotic protein bnip3. Knockdown of CH OP and/or bnip3 expression via RNAi targeting significantly attenuated the death-promoting effects of bortezomib. Thus, bortezomib inhibits prosurvival autophagy, in addition to its known function in blocking the proteasome, and is cytotoxic to hormonally treated ER+ breast cancer cells. These findings indicate that combining a proteasome inhibitor like bortezomib with antiestrogen therapy may have therapeutic advantage in the management of

关键词： tamoxifen bortezomib ER stress autophagy protein turnover bnip3 cathepsins

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Autophagy in cancer associated fibroblasts promotes tumor cell survival Role of hypoxia, HIF1 induction and NFκB activation in the tumor stromal microenvironment

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CELL CYCLE 2010年第17期9卷 3515-3533页

作者： Martinez-Outschoorn, Ubaldo E. Trimmer, Casey Lin, Zhao Whitaker-Menezes, Diana Chiavarina, Barbara Zhou, Jie Wang, Chengwang Pavlides, Stephanos Martinez-Cantarin, Maria P. Capozza, Franco Witkiewicz, Agnieszka K. Flomenberg, Neal Howell, Anthony Pestell, Richard G. Caro, Jaime Lisanti, Michael P. Sotgia, Federica Thomas Jefferson Univ Jefferson Stem Cell Biol & Regenerat Med Ctr Philadelphia PA 19107 USA Thomas Jefferson Univ Dept Med Oncol Philadelphia PA 19107 USA Thomas Jefferson Univ Dept Stem Cell Biol & Regenerat Med Philadelphia PA 19107 USA Thomas Jefferson Univ Kimmel Canc Ctr Dept Canc Biol Philadelphia PA 19107 USA Thomas Jefferson Univ Div Nephrol Dept Med Philadelphia PA 19107 USA Thomas Jefferson Univ Jefferson Ctr Pancreat Biliary & Related Canc Dept Pathol Philadelphia PA 19107 USA Thomas Jefferson Univ Div Hematol Dept Med Cardeza Fdn Philadelphia PA 19107 USA Univ Manchester Manchester Breast Ctr Manchester M13 9PL Lancs England Univ Manchester Breakthrough Breast Canc Res Unit Sch Canc Enabling Sci & Technol Paterson Inst Canc ResManchester Acad Hlth Sci C Manchester M13 9PL Lancs England

Recently, using a co-culture system, we demonstrated that MCF7 epithelial cancer cells induce oxidative stress in adjacent cancer-associated fibroblasts, resulting in the autophagic/lysosomal degradation of stromal caveolin-1 (Cav-1). However, the detailed signaling mechanism(s) underlying this process remain largely unknown. Here, we show that hypoxia is sufficient to induce the autophagic degradation of Cav-1 in stromal fibroblasts, which is blocked by the lysosomal inhibitor chloroquine. Concomitant with the hypoxia-induced degradation of Cav-1, we see the upregulation of a number of well-established autophagy/mitophagy markers, namely LC3, ATG16L, bnip3, bnip3L, HIF-1 alpha and NF kappa B. In addition, pharmacological activation of HIF-1 alpha drives Cav-1 degradation, while pharmacological inactivation of HIF-1 prevents the downregulation of Cav-1. Similarly, pharmacological inactivation of NF kappa B-another inducer of autophagy-prevents Cav-1 degradation. Moreover, treatment with an inhibitor of glutathione synthase, namely BSO, which induces oxidative stress via depletion of the reduced glutathione pool, is sufficient to induce the autophagic degradation of Cav-1. Thus, it appears that oxidative stress mediated induction of HIF1- and NF kappa B-activation in fibroblasts drives the autophagic degradation of Cav-1. In direct support of this hypothesis, we show that MCF7 cancer cells activate HIF-1 alpha- and NF kappa B-driven luciferase reporters in adjacent cancer-associated fibroblasts, via a paracrine mechanism. Consistent with these findings, acute knock-down of Cav-1 in stromal fibroblasts, using an siRNA approach, is indeed sufficient to induce autophagy, with the upregulation of both lysosomal and mitophagy markers. How does the loss of stromal Cav-1 and the induction of stromal autophagy affect cancer cell survival? Interestingly, we show that a loss of Cav-1 in stromal fibroblasts protects adjacent cancer cells against apoptotic cell death. Thus, auto

关键词： caveolin-1 autophagy bnip3 cancer associated fibroblasts HIF1 hypoxia LC3 mitophagy NF kappa B oxidative stress predictive biomarker TIGAR tumor stroma

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脑缺血后海马CA1区caspase非依赖性凋亡相关蛋白表达水平的改变

脑缺血后海马CA1区caspase非依赖性凋亡相关蛋白表达水平的改变

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中国神经科学学会第九届全国学术会议暨第五次会员代表大会

作者：张明海方莹莹李树基朱心红高天明南方医科大学基础医学院神经生物学教研室

目的脑缺血后迟发性神经元死亡的发生机制主要为凋亡,以往的研究表明caspase依赖性机制在这一过程中起重要作用,最近有越来越多的研究表明caspase非依赖性机制也参与了迟发性神经元死亡,但目前对caspase非依赖性细胞凋亡的调节机制尚不... 详细信息

目的脑缺血后迟发性神经元死亡的发生机制主要为凋亡,以往的研究表明caspase依赖性机制在这一过程中起重要作用,最近有越来越多的研究表明caspase非依赖性机制也参与了迟发性神经元死亡,但目前对caspase非依赖性细胞凋亡的调节机制尚不明确,本研究探讨了caspase非依赖性凋亡相关蛋白Bcl-2与腺病毒E1B-19K相互作用蛋白3(bnip3)和凋亡诱导因子(AIF)在脑缺血后海马CA1区的表达的改变。方法制作大鼠全脑缺血/再灌注模型。通过Westen blot方法观察bnip3及AIF在缺血后海马CA1区全细胞、线粒体及核蛋白水平的表达情况。结果 (1)脑缺血/再灌注后bnip3在海马CA1区全细胞及线粒体中的表达水平上调,提示脑缺血诱导了bnip3转位至线粒体。(2)脑缺血/再灌注后AIF在海马CA1区全细胞中及细胞核内表达水平上调,而在线粒体及细胞质部分的蛋白水平下调,并且AIF在线粒体中表达水平下调的时间点晚于bnip3在线粒体中表达水平上调的时间点,提示AIF发生了从线粒体到细胞核的转位,AIF的核转位可能是由bnip3介导的。结论本研究结果提示脑缺血可诱导海马神经元bnip3上调并转位到线粒体,继而可能引起AIF由线粒体释放转位至细胞核,最终导致神经元的死亡。

关键词：脑缺血海马CA1区线粒体 bnip3 AIF caspase非依赖性凋亡

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bnip3基因在喉癌中的表达及意义

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中国老年学杂志 2008年第6期28卷 584-585页

作者：袁彤王苹杜宝东吉林大学第一医院吉林长春130021

目的探讨bnip3基因在喉癌中的表达及意义。方法选择喉鳞状细胞癌患者68例,12例声带息肉伴鳞状上皮增生及14例正常喉黏膜组织,采用免疫组化(S-P)法检测其中bnip3蛋白的表达,同时检测HIF-1α蛋白的表达。结果bnip3蛋白主要表达在肿瘤细胞... 详细信息

目的探讨bnip3基因在喉癌中的表达及意义。方法选择喉鳞状细胞癌患者68例,12例声带息肉伴鳞状上皮增生及14例正常喉黏膜组织,采用免疫组化(S-P)法检测其中bnip3蛋白的表达,同时检测HIF-1α蛋白的表达。结果bnip3蛋白主要表达在肿瘤细胞细胞浆和胞核,HIF-1α表达主要在细胞浆和/或细胞核,均为棕黄至棕黑色颗粒。喉癌中bnip3的表达明显较高于对照组,68例喉癌有40例表达(58.8%);在12例增生有10例阳性表达(83.3%);bnip3的表达与HIF-1α的表达呈正相关,与淋巴结转移近似相关,与肿瘤分化程度、浸润深度无显著相关。Kaplan-Merier生存分析提示bnip3表达阴性组的累计生存情况较阳性组差。结论bnip3基因在喉癌中高表达,可作为判断喉癌预后的指标。

关键词： bnip3 喉癌免疫组化

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Nix, a receptor protein for mitophagy in mammals

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AUTOPHAGY 2010年第3期6卷 433-435页

作者： Kanki, Tomotake Kyushu Univ Grad Sch Med Sci Dept Clin Chem & Lab Med Fukuoka 812 Japan

Mitochondria are important organelles that supply energy to the cell. However, these organelles are also the major source of cellular reactive oxygen species (ROS). Thus, the elimination of damaged or excess mitochondria is essential for maintaining cellular homeostasis. Selective autophagy of mitochondria (mitophagy) plays an important role in the quality control of mitochondria. However, little is known about the molecular mechanism of mitophagy in mammalian cells. Nix is a mitochondrial outer membrane protein that is required for mitochondrial clearance during erythrocyte maturation. Recently, it was reported that Nix is a mitochondrial receptor that can directly connect to one of the autophagic machinery components, the Atg8 homologs LC3 and GABARAP.

关键词： Nix bnip3 bnip3L mitochondria autophagy mitophagy reticulocyte

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bnip3 subfamily BH3-only proteins: mitochondrial stress sensors in normal and pathological functions

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ONCOGENE 2008年第12-2-2008期27卷 S114-S127页

作者： Chinnadurai, G. Vijayalingam, S. Gibson, S. B. St Louis Univ Sch Med Inst Mol Virol Doisy Res CtrMed Ctr St Louis MO 63104 USA Univ Manitoba Manitoba Inst Cell Biol Winnipeg MB Canada

The bnip3 subfamily of BH3-only proteins consists of bnip3 and bnip3-like (bnip3L) proteins. These proteins form stable homodimerization complexes that localize to the outer membrane of the mitochondria after cellular stress. This promotes either apoptotic or non-apoptotic cell death such as autophagic cell death. Although the mammalian cells contain both members of this subfamily, the genome of Caenorhabditis elegans codes for a single bnip3 ortholog, cebnip3, which shares homology in the transmembrane (TM) domain and in a conserved region close to the BH3 domain of mammalian bnip3 protein. The cell death activities of bnip3 and bnip3L are determined by either the BH3 domain or the C-terminal TM domain. The TM domain of bnip3 is unique, as it is capable of autonomous stable dimerization and contributes to mitochondrial localization of bnip3. In knockout mouse models, bnip3L was shown to be essential for normal erythrocyte differentiation and hematopoietic homeostasis, whereas bnip3 plays a role in cellular responses to ischemia/reperfusion injury in the heart. Both bnip3 and bnip3L play a role in cellular responses to stress. Under hypoxia, both bnip3 and bnip3L expression levels are elevated and contribute to hypoxia-induced cell death. In addition, these proteins play critical roles in disease states. In heart disease, both bnip3 and bnip3L play a critical role in cardiomyocyte cell death following ischemic and non-ischemic injuries. In cancer, expression of bnip3 and bnip3L is downregulated by promoter hypermethylation or by homozygous deletion of the gene locus in certain cancers, whereas their expression was increased in other cancers. In addition, bnip3 expression has been correlated with poor prognosis in some cancers. The results reviewed here suggest that bnip3 and bnip3L may be novel therapeutic targets for intervention because of their pathological roles in regulating cell death in disease states. Oncogene (2009) 27, S114-S127;doi: 10.1038/onc.2009.49

关键词： bnip3 bnip3L apoptosis autophagy cancer cardiomyopathies

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