M E Peter

..Our understanding of the regulators of the extrinsic apoptosis signalling pathway biochemically may provide the means to design drugs to correct the imbalance between apoptosis and proliferation, as found in many diseases...

..Necrotic cells release HMGB1 as a danger signal to activate the immune system. In this issue of Immunity, Kazama et al. (2008) identify a mechanism that determines whether HMGB1 is tolerogenic or immunogenic...

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..A number of proteins have been reported to regulate formation or activity of the DISC. This review discusses recent developments in this area of death receptor research...

..Recent evidence suggests, however, that CD95 mediates not only apoptosis but also diverse nonapoptotic functions depending on the tissue and the conditions...

..I propose that steps of this process are driven by specific changes in the expression of let-7 and miR-200 family members...

..These findings provide new insight into the network of transcription factors and miRNAs that regulate cancer stem cells...

..This study ushers in a new era of miRNA research that focuses on networks more than on individual connections between miRNA and strongly predicted targets...

..Our data suggest that it is possible to overcome the CD95 apoptosis resistance of many tumor cells that do not efficiently form a DISC through noncanonical activation of the caspase-8 proenzyme...

..This review will focus on recent insights into the mechanisms of the two different types of CD95 signaling pathways, and will introduce miRNAs as regulators of death receptor signaling...

..Our data suggest that monoubiquitination of DEDD regulates both its cytoplasmic localization and its proapoptotic potential and that IAP proteins can regulate DEDD's ubiquitination status...

..Here, we summarize the role of miRNAs and their targets in contributing to human cancers and their function as regulators of apoptotic pathways and the immune system...

..We propose a model in which NF-kappaB is generally activated in certain cells but may have different functions depending on whether cells are programmed to die or to survive...

..This could become highly relevant during chemotherapy, which can cause upregulation of CD95 ligand by both tumor and nontumor cells...

..The regulation of let-7 expression, cancer-relevant let-7 targets, and the relationship between let-7 and drug sensitivity are highlighted...

..It appears that caspases play a much more fundamental role in cells than originally expected...

..These data identify loss of let-7 expression as a marker for less differentiated cancer...

..Our analysis reveals fundamental differences in programs of gene expression between type I and type II cells and could impact the way actin- and microtubule-disrupting antitumor agents are used in tumor therapy...

..Conversely, inhibition of miR-200 reduced E-cadherin expression, increased expression of Vimentin, and induced EMT. Our data identify miR-200 as a powerful marker and determining factor of the epithelial phenotype of cancer cells...

..The DED in DEDD therefore represents a novel domain that is structurally similar to other DEDs but functionally different from classical DEDs found in FADD or caspase-8...

..In contrast wild-type grafts were rapidly eliminated in autoimmune recipients. Our data provide strong support for a major role of CD95 in the destruction of islets in autoimmune mice...

..The late repression of HMGA2 by let-7 during embryonic development, and the early reexpression of HMGA2 during cancer development, is in line with the hypothesis that cancer development represents a case of reverse embryogenesis...

..However, recent work has ascribed multiple non-apoptotic activities to these receptors and/or the signaling components of the DISC...

..These results demonstrate that CD95 has a growth-promoting role during tumorigenesis and indicate that efforts to inhibit its activity rather than to enhance it should be considered during cancer therapy...

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..Since the first complex can activate survival signals and influence the activity of the second complex, this mechanism provides a checkpoint to control the execution of apoptosis...

..This review focuses on recent developments in the delineation of the biochemistry and the physiological function of the two CD95 pathways...

..Oncogene (2003) 22, 8634-8644. doi:10.1038/sj.onc.1207103..

..Our data suggest that DEDD represents a novel scaffold protein that directs the effector caspase-3 to certain substrates facilitating their ordered degradation during apoptosis...

..Although some of these studies have considerably influenced our view on the role of the CD95/CD95L system compelling evidence for an involvement of the CD95/CD95L system in the physiological epithelial cell turnover is lacking...

..This review critically discusses the data on the possible function of CD95 as an apoptosis-inducing receptor in IBD and discusses alternative mechanisms for epithelial cell loss in IBD...

..The data indicate that the signal initiation by CD95 is a complex process actively regulated at various levels, providing a number of new drug targets to specifically modulate CD95 signaling...

..Data revealed that CD95 is palmitoylated on cysteine 199. This lipid modification enhances receptor aggregation to the high molecular weight DISC...

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..The data suggest that CD95 is linked to the cytoskeleton in different ways in the two cell types and that they have adapted to different levels of active caspase-8 generated at the activated receptor...

..Mutations in CD95 may eliminate the tumour-suppressive function of CD95, at the same time allowing induction of survival or proliferative pathways, which could contribute to the increased risk for lymphoma seen in ALPS type Ia patients...

..These findings identify Gadd45 beta as a critical mediator of the prosurvival response to CD40 stimulation and provide important new insights into the apoptotic mechanism that is triggered by Fas in B cells...

..Our data suggest that a substantial part of the growth inhibitory activities of let-7 comes from suppressing the expression of IMP-1. LOGs could be novel therapeutic targets and potential biomarkers for cancer treatment...

..SNARK therefore represents an NF-kappaB-regulated anti-apoptotic gene that contributes to the tumor-promoting activity of CD95 in apoptosis-resistant tumor cells...

..Our data demonstrate that SDS-stable forms of CD95 are the sites of apoptosis initiation and represent an important early step in apoptosis signaling through CD95 before activation of caspases...

..Our data represent the first case of CD95 protecting from developing a solid cancer...

..Our data provide new insights into the mechanisms by which apoptotic proteins participate to mitogenic signals during the G(1) phase...

..Hence, the subcellular localization and internalization pathways of CD95 play important roles in controlling activation of distinct signaling cascades to determine divergent cellular fates...

..c-FLIP(L) acts as an apoptosis inhibitor only at high ectopic expression levels. Thus, c-FLIP(L) defines a novel type of caspase regulator, distinct from the death adaptors, that can either promote or inhibit apoptosis...

..In addition to regulating cell survival and cytokine maturation, caspases may be involved in regulating cell differentiation, cell proliferation, spreading and receptor internalization...

..Thus, such inclusions do not merely accumulate disrupted cytokeratins but also sequestrate potentially noxious proteins that could injure healthy neighboring cells...

..These results reveal the key steps leading to the activation of procaspase-8 by oligomerization...