D R Green

..This idea has recently been challenged, and here we review the evidence for and against a role for FasL in immune privilege...

..They propose a model for initiation of apoptosis in which mitochondria and caspases engage in a self-amplifying pathway of mutual activation...

....

..Together, these data suggest that caspase-3 is the primary inactivator of DFF45/ICAD and therefore the primary activator of apoptotic DNA fragmentation...

..Bcl-2 blocks the rapid destruction of targets by granzyme B by blocking mitochondrial involvement in the process...

..Lack of APAF-1 activity correlated in some but not all cell lines with resistance to apoptosis. These data suggest that regulation of APAF-1 activity may be important for apoptosis regulation in some ovarian cancers...

..This review discusses recent advances on the role of mitochondria and cytochrome c in the central pathway leading to apoptotic cell death...

..Thus, these results demonstrate that FasL-mediated death of IEC by IEL is a major mechanism of IEC apoptosis seen in GVHD...

..Hence, in oncogene-expressing MEF p53 induces apoptosis by BH3 protein-dependent caspase activation...

..The FasL gene, which is often transcriptionally inactive, becomes activated in many forms of transcription/translation dependent apoptosis. Here we will discuss FasL as a candidate death gene...

..host disease, and hepatitis. Here we review the Fas/FasL system and the evidence that it is involved in the pathogenesis of liver and gastrointestinal diseases...

..c-GFP. We conclude that there is a general mechanism responsible for cytochrome c release that proceeds in a single step that is independent of changes in DeltaPsi(m)...

..Our data suggest that cytochrome c release, initiated by the action of caspases on a cytosolic substrates, may act to amplify a caspase cascade during apoptosis...

..The end result of either pathway is caspase activation and the cleavage of specific cellular substrates, resulting in the morphologic and biochemical changes associated with the apoptotic phenotype...

....

..In contrast, the transcription factor AP-1 is not required for activation-induced FasL promoter activity. These results define a role for NF-kappaB in mediating FasL expression during T cell activation...

..These data implicate calpain as a potential regulator of caspases and suggest that calpain, not caspases, promotes apoptosis-like events during platelet activation...

..Susceptibility of aSMase(-/-) mice to anti-Fas antibody was demonstrated with higher antibody doses (>/=4 microg/25 g mouse). These data indicate a role for aSMase in Fas-mediated cell death in some but not all tissues...

..Additionally, factors affecting the pro- and anti-inflammatory effects of CD95L point to a balance of cytokines and growth factors...

..Nevertheless, the end result of either pathway is caspase activation and the cleavage of specific cellular substrates, resulting in the morphological and biochemical changes associated with the apoptotic phenotype...

..Our findings identify a precise physiological role for c-Myc in the induction of apoptosis as a transcriptional regulator of the FasL gene...

..The apparent absence of mitochondrial outer membrane permeabilization (MOMP) in Drosophila apoptosis may permit the cell to thrive when caspase activation is disrupted...

..Thus, some immune responses induce FasL in nonlymphoid tissues, which in turn kills activated lymphocytes, leading to peripheral T cell deletion...

..This article discusses the functional interactions between the stress response and the apoptotic cell death pathway and how these might impact on determining cellular survival...

..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...

....

....

..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...

....

..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...

..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...

....

..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...

..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...

..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...

..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...

..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...

..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...

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

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

....

..Knockdown was assessed qualitatively with in situ hybridizations for both genes. Quantitative PCR and caspase activity assays were used as a quantitative measure of knockdown for acasp...

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

..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...

..This paves the way for establishing new lower metazoan model systems for the study of apoptosis...

..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...

..In mice, caspase-12 deficiency confers resistance to sepsis and its presence exerts a dominant-negative suppressive effect on caspase-1, resulting in enhanced vulnerability to bacterial infection and septic mortality...

..Concepts reviewed here include caspase activation, death pathways, and crosstalk between death ligands and their receptors...

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

..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 a unified caspase activation hypothesis whereby apical caspases are activated by dimerization of monomeric zymogens...

....

..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 contrast, IKKalpha controls the induction by LTbetaR ligation of chemokines and cytokines involved in lymphoid organogenesis, including SLC, BLC, ELC, SDF1, and BAFF...

....

..Bcl-2 overexpressing cells succumb to Vpr-induced apoptosis. These studies illustrate that Vpr induces a mitochondria-dependent apoptotic pathway that is distinct from apoptosis driven by the Fas-FasL pathway...

....

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

..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...

....

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

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

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

..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...

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

..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...

..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...

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

..These results support a role for Egr family members in nonlymphoid expression of FasL, TRAIL, and TNF...

..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...