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To die or not to die, for cell that is the question

  • Hefei National Laboratory for Physical Sciences at Microscale, and Laboratory for Tumor and Apoptosis, School of Life Science, University of Science and Technology of China, Hefei 230027, China

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  • Corresponding author: WU Mian, E-mail: wumian@ustc.edu.cn
  • Received Date: 28 June 2008
  • Rev Recd Date: 28 July 2008
  • Publish Date: 31 August 2008
    Abstract

  • Abstract

    Apoptosis, or the programmed cell death, is employed by eukaryotes to eliminate damaged or unwanted cells tomaintain homeostasis. Unlike necrosis, apoptosis is an active, genetically controlled sequence of events which involve the activation, expression and regulation of multiple genes. Apoptosis reflects a strategy of cells to adapt to a changing environment rather than passive self-damage under pathological conditions. Malfunction of apoptosis, either being “too much” or “too little”, has been implicated in various diseases, including tumorigenesis. Due to the critical roles apoptosis play in maintaining tissue homeostasis, pro- and anti-apoptotic signals are carefully balanced within cells. This balance is achieved through the products of a series of apoptosis-related genes, including the anti-apoptotic IAP (inhibitor of apoptosis protein) family, the pro-apoptotic caspase protease family, the p53 tumor suppressor as well as recently characterized non-coding RNAs such as microRNAs. Through directly or indirectly interacting with each other, these factors constitute a complex signaling network whose overall function determines the progress of apoptosis and ultimately, the fate of the cell. Defining the molecular mechanisms by which each factor contributes to apoptosis will not only deepen our understanding of cell physiology and the origin of life, but also enable a more rational approach to anticancer drug design and therapy.

    Abstract

    Apoptosis, or the programmed cell death, is employed by eukaryotes to eliminate damaged or unwanted cells tomaintain homeostasis. Unlike necrosis, apoptosis is an active, genetically controlled sequence of events which involve the activation, expression and regulation of multiple genes. Apoptosis reflects a strategy of cells to adapt to a changing environment rather than passive self-damage under pathological conditions. Malfunction of apoptosis, either being “too much” or “too little”, has been implicated in various diseases, including tumorigenesis. Due to the critical roles apoptosis play in maintaining tissue homeostasis, pro- and anti-apoptotic signals are carefully balanced within cells. This balance is achieved through the products of a series of apoptosis-related genes, including the anti-apoptotic IAP (inhibitor of apoptosis protein) family, the pro-apoptotic caspase protease family, the p53 tumor suppressor as well as recently characterized non-coding RNAs such as microRNAs. Through directly or indirectly interacting with each other, these factors constitute a complex signaling network whose overall function determines the progress of apoptosis and ultimately, the fate of the cell. Defining the molecular mechanisms by which each factor contributes to apoptosis will not only deepen our understanding of cell physiology and the origin of life, but also enable a more rational approach to anticancer drug design and therapy.
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    • References(13)
  • [1]
    Lockshin R A, Williams C M. Programmed cell death I: Cytology of degeneration in the intersegmental muscles of the Pernyi Silkmoth[J]. J Insect Physiol, 1965,11:123-133.
    [2]
    Kerr J F, Wyllie A H, Currie A R. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics[J]. Br J Cancer, 1972,26:239-257.
    [3]
    Song Z, Yao X B, Wu M. Direct interaction between survivin and Smac/DIABLO is essential for the anti-apoptotic activity of survivin during taxol-induced apoptosis[J]. J Biol Chem, 2003,278(25):23 130-23 140.
    [4]
    Song Z, Liu S, Wu M, et al. A single amino acid change (Asp53→Ala53) converts Survivin from anti-apoptotic to pro-apoptotic[J]. Mol Biol Cell, 2004,15(3):1 287-1 296.
    [5]
    Ma L, Huang Y, Wu M, et al. Livin promotes Smac/DIABLO degradation by ubiquitin-proteasome pathway[J]. Cell Death Differ, 2006,13(12):2 079-2 088.
    [6]
    Mei Y, Du W, Wu M, et al. Puma*Mcl-1 interaction is not sufficient to prevent rapid degradation of Mcl-1[J]. Oncogene, 2005,24(48):7 224-7 237.
    [7]
    Yao Zhan, Duan Shanshan, Wu Mian, et al. Death effector domain DEDa, a self-cleaved product of Caspase-8/Mch5,translocates to the nucleus by binding to ERK1/2 and up-regulates procaspase-8 expression via a p53-dependent mechanism[J]. EMBO J, 2007,26:1 068-1 080.
    [8]
    Jiang P, Du W, Wu M, et al. The bad guy cooperates with good cop p53: Bad is transcriptionally up-regulated by p53 and forms a Bad/p53 complex at the mitochondria to induce apoptosis[J]. Mol Cell Biol, 2006,26(23):9 071-9 082.
    [9]
    Xie W, Jiang P, Wu M, et al. Novel link between E2F1 and Smac/DIABLO: Proapoptotic Smac/DIABLO is transcriptionally upregulated by E2F1[J]. Nucleic Acids Res, 2006,34(7):2 046-2 055.
    [10]
    Yang Y, Ma J, Wu M, et al. Nucleocytoplasmic shuttling of receptor-interacting protein 3 (RIP3): Identification of novel nuclear export and import signals in RIP3[J]. J Biol Chem, 2004,279(37):38 820-38 829.
    [11]
    Duan Shanshan, Yao Zhan, Wu Mian, et al. Phosphorylation of Pirh2 by Calmodulin-dependent kinase II impairs its ability to ubiquitinate p53[J]. EMBO J, 2007,26(13):3 062-3 074.
    [12]
    Mei Yide, Xie Chongwei, Wu Mian, et al. Siah-1Sa novel splice variant of Siah-1 (seven in absentia homolog), counteracts Siah-1-mediated downregulation of β-catenin[J]. Oncogene, 2007,26(43):6 319-6 331.
    [13]
    Song Z Y, Wu M. Identification of a novel nucleolar localization signal and a degradation signal in Survivin-deltaEx3: A potential link between nucleolus and protein degradation[J]. Oncogene, 2005,24(16):2 723-2 734.
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    [1]
    Lockshin R A, Williams C M. Programmed cell death I: Cytology of degeneration in the intersegmental muscles of the Pernyi Silkmoth[J]. J Insect Physiol, 1965,11:123-133.
    [2]
    Kerr J F, Wyllie A H, Currie A R. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics[J]. Br J Cancer, 1972,26:239-257.
    [3]
    Song Z, Yao X B, Wu M. Direct interaction between survivin and Smac/DIABLO is essential for the anti-apoptotic activity of survivin during taxol-induced apoptosis[J]. J Biol Chem, 2003,278(25):23 130-23 140.
    [4]
    Song Z, Liu S, Wu M, et al. A single amino acid change (Asp53→Ala53) converts Survivin from anti-apoptotic to pro-apoptotic[J]. Mol Biol Cell, 2004,15(3):1 287-1 296.
    [5]
    Ma L, Huang Y, Wu M, et al. Livin promotes Smac/DIABLO degradation by ubiquitin-proteasome pathway[J]. Cell Death Differ, 2006,13(12):2 079-2 088.
    [6]
    Mei Y, Du W, Wu M, et al. Puma*Mcl-1 interaction is not sufficient to prevent rapid degradation of Mcl-1[J]. Oncogene, 2005,24(48):7 224-7 237.
    [7]
    Yao Zhan, Duan Shanshan, Wu Mian, et al. Death effector domain DEDa, a self-cleaved product of Caspase-8/Mch5,translocates to the nucleus by binding to ERK1/2 and up-regulates procaspase-8 expression via a p53-dependent mechanism[J]. EMBO J, 2007,26:1 068-1 080.
    [8]
    Jiang P, Du W, Wu M, et al. The bad guy cooperates with good cop p53: Bad is transcriptionally up-regulated by p53 and forms a Bad/p53 complex at the mitochondria to induce apoptosis[J]. Mol Cell Biol, 2006,26(23):9 071-9 082.
    [9]
    Xie W, Jiang P, Wu M, et al. Novel link between E2F1 and Smac/DIABLO: Proapoptotic Smac/DIABLO is transcriptionally upregulated by E2F1[J]. Nucleic Acids Res, 2006,34(7):2 046-2 055.
    [10]
    Yang Y, Ma J, Wu M, et al. Nucleocytoplasmic shuttling of receptor-interacting protein 3 (RIP3): Identification of novel nuclear export and import signals in RIP3[J]. J Biol Chem, 2004,279(37):38 820-38 829.
    [11]
    Duan Shanshan, Yao Zhan, Wu Mian, et al. Phosphorylation of Pirh2 by Calmodulin-dependent kinase II impairs its ability to ubiquitinate p53[J]. EMBO J, 2007,26(13):3 062-3 074.
    [12]
    Mei Yide, Xie Chongwei, Wu Mian, et al. Siah-1Sa novel splice variant of Siah-1 (seven in absentia homolog), counteracts Siah-1-mediated downregulation of β-catenin[J]. Oncogene, 2007,26(43):6 319-6 331.
    [13]
    Song Z Y, Wu M. Identification of a novel nucleolar localization signal and a degradation signal in Survivin-deltaEx3: A potential link between nucleolus and protein degradation[J]. Oncogene, 2005,24(16):2 723-2 734.
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