Douglas Green

..We consider six impossible things and what we might be able to do about them, provided they are believed by lunchtime or, with practice, before breakfast...

..Here, we attempt to explain why there are so many different forms of cell death, and propose a distinction between active death that constitutes 'suicide' versus 'sabotage'...

..In this issue of Molecular Cell, Wang et al. (2008) propose another function for Bcl2: the inhibition of DNA repair by nonhomologous end-joining...

..Consequently, a central problem in immunology is to understand how the immune system determines whether cell death is immunogenic, tolerogenic or 'silent'...

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..The discovery of three new target genes for p53 reveals unexpected functions for this tumor suppressor in the regulation of glucose metabolism and autophagy...

..Two recent studies highlight competition between hematopoietic stem cells based on p53. These findings have implications for both normal homeostasis and tumorigenesis...

..Here, we discuss an emerging view, proposed by Certo et al. in this issue of Cancer Cell, on how these interactions result in MOMP and apoptosis...

..New findings by Hughes et al. (2008), Hutcheson et al. (2008), and Weant et al. (2008) highlight the roles of apoptosis regulators Bim and Fas in the contraction phase of T cell responses and reveal consequences of failure of this process...

..Thus, a combination of mitochondrial dysfunction and insufficient autophagy may contribute to multiple aging-associated pathologies...

..In this review, we will lay out the evidence as it now stands, reinterpreting earlier observations in light of new clues and considering where the investigation might lead...

..Here we discuss the different modes of cell death as they relate to this rapidly evolving field...

..An emerging area of research unravels additional activities of p53 in the cytoplasm, where it triggers apoptosis and inhibits autophagy. These previously unknown functions contribute to the mission of p53 as a tumour suppressor...

..Possible links between these two forms of cellular "eating" represent a new dimension in host defense...

..Thus, iMOMP provides a critical source of intact mitochondria that permits cellular survival following MOMP...

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..Here we will define these interactions and discuss our experiments that suggest PUMA cooperates with direct activator proteins to efficiently induce MOMP and apoptosis...

..Furthermore, we identify Hsp90alpha as a key negative regulator of heat shock-induced caspase-2 activation...

..Our results demonstrate a pathway for survival of activated T cells through NF-κB-induced Mdm2, which blocks Bim-dependent apoptosis through binding and inhibition of p73...

..MOMP typically leads to cell death irrespective of caspase activity by causing a progressive decline in mitochondrial function, although cells can survive this under certain circumstances, which may have pathophysiological consequences...

..We discuss these techniques here and highlight the advantages and drawbacks of using such approaches to study apoptosis...

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..The timing and extent of AIF release makes it unlikely that it is involved in the induction of apoptosis, either upstream or downstream of mitochondrial outer membrane permeabilization...

..Our data show that the induction of apoptosis by inhibition of the anti-apoptotic BCL-2 repertoire requires "covert" levels of direct activators of BAX and BAK at the OMM...

..Here we will discuss the mechanisms and functions of the BCL-2 family in the context of these pathways, highlighting the complex integration and regulation of the BCL-2 family in cell fate decisions...

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..These data suggest that the PB1-F2 protein contributes to the virulence of pandemic strains when the PB1 gene segment is recently derived from the avian reservoir...

..In this review, we discuss recent views on how Toll-like receptors direct microbes to final destruction by regulating the different pathways that lead to the lysosome...

..Next, the cells are induced to undergo apoptosis and continuously imaged. Finally, quantitative kinetic analysis of various apoptotic processes is performed postimaging...

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..Proper regulation of these mitochondrial functions is vitally important for the life and death of the cell and for the organism as a whole...

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..The results demonstrate that the control of MCL-1 stability by GSK-3 is an important mechanism for the regulation of apoptosis by growth factors, PI3K, and AKT...

..As well as its role in canonical intrinsic apoptosis, cytochrome c amplifies signals that are generated by other apoptotic pathways and participates in certain non-apoptotic functions...

..Mutant Bcl-xL that bound p53, but not PUMA, rendered cells resistant to p53-induced apoptosis irrespective of PUMA expression. Thus, PUMA couples the nuclear and cytoplasmic proapoptotic functions of p53...

..In parallel, p53 can release pro-apoptotic Bcl-2 proteins sequestered by Bcl-x(L). These data suggest that cytoplasmic p53 functions analogously to the BH3-only proteins, a subset of pro-apoptotic Bcl-2 proteins...

..Therefore, caspase cleavage of NDUFS1 is required for several mitochondrial changes associated with apoptosis...

..The general rules governing the pathophysiology of MOMP and controversial issues regarding its regulation are discussed...

..Thus, BH3 domains do not necessarily activate multidomain pro-apoptotic proteins directly but promote apoptosis by releasing active multidomain pro-apoptotic proteins from their anti-apoptotic counterparts...

..We propose that when p53 accumulates in the cytosol, it can function analogously to the BH3-only subset of proapoptotic Bcl-2 proteins to activate Bax and trigger apoptosis...

..We conclude that mitochondrial protein release in apoptosis can be mediated by supramolecular openings in the outer mitochondrial membrane, promoted by BH3/Bax/lipid interaction and directly inhibited by Bcl-x(L)...

..In this model, the simple inhibition of antiapoptotic functions is insufficient to induce apoptosis unless a direct activator of Bax or Bak is present...

..Hence, pharmacologic p53 modulators can activate a transcription-independent apoptotic program...

..These results demonstrate the central role of ARK in stress-induced apoptosis, which appears to act independently of cytochrome c. Apoptosis induced by Reaper or Grim can proceed via a distinct pathway, independent of ARK...

..It is still unclear how these proteins are released from the mitochondria. Recent advances in our knowledge of mitochondrial outer-membrane permeabilization and the consequences of this event on mitochondria will be discussed...

..Here we will explore what is currently known about TIPA learned from various p53 mutants and truncations, along with discussing several proposed mechanisms...

..These data demonstrate that nonlymphoid FasL is expressed in response to peripheral T cell activation and participates in the regulation of T cells that infiltrate peripheral tissues...

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..In addition, the intricacies of the mitochondrial role in apoptosis are starting to unravel with reports of novel proteins, such as Smac/DIABLO, and old proteins, such as heat shock proteins, playing new roles in regulating cell death...

..Nuclear Factor kappa-B appears to be required to prevent p73-induced apoptosis triggered by primary T cell activation. Here we explore what this state of affairs might do for the regulation of the immune system...

..Thus, we provide molecular and functional evidence for negative signaling by death receptors...

..Both events are induced by proapoptotic members of the Bcl-2 family and appear to be separable...

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..The secondary traits of diverse neoplasms are a consequence of cell proliferation, tissue expansion, and other outcomes of this platform...

..The data are consistent with a model in which Caspase-2 induces apoptosis via cleavage of Bid at D59 and the subsequent engagement of the mitochondrial (intrinsic) pathway...

..The results provide a mechanism for a well-established method of inducing immunologic unresponsiveness...

..Moreover, loss of Apaf-1 did not promote oncogene-induced transformation of mouse embryo fibroblasts. Thus, Apaf-1 and caspase-9 do not suppress c-myc-induced lymphomagenesis and embryo fibroblast transformation...

..Some of them are potentially contributory to this lectin's proapoptotic function and these include redox-related genes monoamine oxidase B, ryanodine receptor 2, and glutathione S-transferase Mu 3...

..Our results support an emerging paradigm, wherein the activation of Bax or Bak and the blockade of antiapoptotic Bcl-2 proteins are pivotal steps in the mitochondrial pathway of apoptosis...

..This approach unambiguously identifies the apical caspase activated in response to apoptotic stimuli, and establishes caspase-2 as a proximal mediator of heat shock-induced apoptosis...

..In summary, GA binding to TfR induces a unique signal leading to rapid apoptosis of tumor cells. These results suggest that GA may provide an additional approach for targeting the TfR and its use in cancer therapy...

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..The emerging, if preliminary, perspective these new studies provide may represent either a refinement of our views of how cells die or, perhaps, the beginnings of what amounts to a reformulation of our ideas...

..These results indicate that the nature and duration of antigenic stimulation regulate the autonomy of CTL expansion via the production of autocrine IL-2...

..Here, we present recent findings and discuss the physiological relevance of caspase-independent cell death...

..Therefore, GAPDH mediates an elevation in glycolysis and enhanced autophagy that cooperate to protect cells from CICD...

..In conclusion, we have identified a key mechanism in the control of p73 protein levels both in normal as well as in stress conditions...

..Swelling occurs only late in apoptosis after release of cytochrome c and loss of the mitochondrial membrane potential...

..Regulation of Trail expression can therefore account for the role of CD4+ T cells in the generation of CD8+ T cell memory and represents a novel mechanism for controlling adaptive immune responses...

..Our findings raise the interesting possibility that mdivi-1 represents a class of therapeutics for stroke, myocardial infarction, and neurodegenerative diseases...

..Our data indicate that BM depletion in acute GVHD is mediated by p53-dependent up-regulation of Fas on BMC, which leads to Fas-dependent depletion and subsequent disease...

..In conclusion, our data support a link between cell cycle progression, activation-induced Fas ligand expression, and apoptosis in T cells...

..The evolutionarily conserved "Chk1-suppressed" pathway defines a novel apoptotic process, whose responsiveness to Chk1 inhibitors and insensitivity to p53 and BCL2 alterations have important implications for cancer therapy...

..In this review, we describe current knowledge of the functions of different Bcl-2 members and their potential roles in disease and immunity...

..Similarly, blocking sites of oxidation in HMGB1 prevented tolerance induction by apoptotic cells. These results suggest that caspase-orchestrated mitochondrial events determine the impact of apoptotic cells on the immune response...

..Concomitant with differentiation is a loss of FoxP3 mRNA and protein. These data demonstrate that FoxP3 levels regulate T cell function, and that FoxP3 itself is dynamically regulated during effector T cell differentiation...

..This novel pathway has fundamental implications for our understanding of T lymphocyte responses under different conditions, and will have impact on our ability to manipulate the immune response. ..

..Successful completion of the proposed work will reveal fundamental new processes in the control of cell life and death. ..

..Our studies will elucidate how the central mechanisms of this mitochondrial-caspase axis control life/death decisions in cells. ..

..The interconnections between these biological events and the overlapping principles that emerge represent an emerging field in biology and biomedical research. ..

..These three goals represent independent and complimentary approaches to the elucidation of the novel apoptotic pathway represented by heat shock and proceeding through the activation of caspase-2 ..

..Our goals represent an integrated approach to understanding the processes of AICD and peripheral deletion and their relationships to the pathways of apoptosis. ..

..In this integrated approach to the problem of p53 function in apoptosis, we will elucidate the roles of p53 in the context of stress-induced apoptosis in mature and developing T cells. ..

..The studies proposed herein will provide mechanistic insights into these functions. ..

..Successful completion of the proposed work will reveal fundamental new processes in the control of cell life and death. ..

..These three goals represent independent and complimentary approaches to the elucidation of the novel apoptotic pathway represented by heat shock and proceeding through the activation of caspase-2 ..

..Together, our studies will secure a mechanistic basis for the function of Hsp70 in the regulation of cell death and cell survival. ..

..Together, these studies will give us insights into the mechanisms whereby T cells induce expression of peripheral, nonlymphoid FasL and the roles this plays in immune homeostasis. ..

..His focus on T lymphocytes is important in the context of understanding how the immune system responds to DNA damage and related stress to remove potentially damaged cells, that could otherwise pose a threat to immune integrity. ..

..Once characterized in detail, the activation of the critical proteases will eventually serve as a biochemical thread by which to trace the molecular events that begin at the surface and result in cell death in the immune system. ..