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Fas ligand (FasL) is a type II transmembrane protein belonging to the tumor necrosis factor family. Its binding to the cognate Fas receptor triggers the apoptosis that plays a pivotal role in the maintenance of immune system homeostasis. The cell deathinducing property of FasL has been associated with its extracellular domain, which can be cleaved off by metalloprotease activity to produce soluble FasL. The fate of the remaining membrane-anchored N-terminal part of the FasL molecule has not been determined. Here we show that post-translational processing of overexpressed and endogenous FasL in T-cells by the disintegrin and metalloprotease ADAM10 generates a 17-kDa N-terminal fragment, which lacks the receptor-binding extracellular domain. This FasL remnant is membrane anchored and further processed by SPPL2a, a member of the signal peptide peptidaselike family of intramembrane-cleaving proteases. SPPL2a cleavage liberates a smaller and highly unstable fragment mainly containing the intracellular FasL domain (FasL ICD). We show that this fragment translocates to the nucleus and is capable of inhibiting gene transcription. With ADAM10 and SPPL2a we have identified two proteases implicated in FasL processing and release of the FasL ICD, which has been shown to be important for retrograde FasL signaling.

The Synechocystis sp. PCC 6803 genome encodes four putative homologues of the AAA protease FtsH, two of which (slr0228 and sll1463) have been subjected to insertional mutagenesis in this study. Disruption of sll1463 had no discernible effect but disruption of slr0228 caused a 60% reduction in the abundance of functional photosystem I, without affecting the cellular content of photosystem II or phycobilisomes. Fluorescence and immunoblotting analyses show reductions in PS I polypeptides and possible structural alterations in the residual PS I, indicating an important role for slr0228 in PS I biogenesis. ß

Glucocorticoids (GCs IntroductionUpon triggering of their T-cell receptor (TCR), resting naive T lymphocytes are activated to elicit an immune response. In contrast, preactivated T cells undergo activation-induced cell death (AICD) in response to the same signal. [1][2][3] Apoptosis by AICD is an important mechanism to down-regulate the number of reactive T cells and to terminate the immune response. 4 The main apoptotic pathway of AICD is mediated by the CD95 (apoptosis antigen-1 [APO-1]/Fas) death receptor system since cell death by TCR restimulation can be blocked almost completely in the presence of reagents that inhibit CD95/CD95L interaction. 1-3 CD95 ligand (CD95L, CD178) is induced upon TCR/CD3 cross-linking and triggers CD95 signaling and subsequently apoptosis. 5 Deregulation of CD95L expression results in several diseases, such as autoimmunity and uncontrolled lymphoproliferation. [6][7][8] The transcriptional regulation of the CD95L promoter upon TCR/CD3 stimulation has been studied extensively. Various transcription factors and regulatory elements have been identified, such as several binding sites for nuclear factor of activated T cells (NF-AT), nuclear factor B (NF-B), activator protein 1 (AP-1), early growth response (Egr) protein, and interferon regulatory factor 1 (IRF-1). 9 The glucocorticoid receptor (GR) is a ligand-dependent transcription factor that acts as a major modulator of the immune system due to its anti-inflammatory and immunosuppressive activities, thus serving a function that is frequently put to use in the treatment of autoimmune disorders, inflammatory diseases, and allergy. In the absence of ligand, the receptor is retained in the cytoplasm in an inactive state forming a large complex that includes chaperones. 10 Upon hormone binding, the GR dissociates from the cytoplasmic complex and translocates into the nucleus. Within the nucleus it acts as a transcriptional activator by binding as a homodimer with high affinity to glucocorticoid responsive DNA elements (GREs). In addition to enhancing the rate of transcription, the GR can also act as a transcriptional repressor by binding to different DNA sequences called negative GREs (nGREs). 11,12 Besides direct DNA binding, the GR can also modulate transcription as a monomer via protein-protein interactions as documented by repressive effects on AP-1 and NF-B 13-15 and activation of signal transducer and activator of transcription 5 (Stat-5). 16 Glucocorticoid (GC) hormones exert their potent antiinflammatory action mainly by inhibition of cytokine gene expression, and hence effectively block the activation of the immune system. 15,17,18 In addition, GCs are potent inducers of apoptosis in thymocytes and in some T-cell hybridomas by DNA bindingdependent transcriptional regulation, whereas peripheral T cells are only weakly sensitive toward GC-induced cell death. Although both GC and TCR stimulation can induce apoptosis in T-cell hybridomas, surprisingly, cell death is strongly reduced when both stimuli are provided simultaneously. 19...

The nuclear receptor superfamily comprises a large group of transcription factors that play a key regulatory role in development and homeostasis of multicellular organisms. A special feature of nuclear receptors is their ability to bind to condensed chromatin templates, which makes them important initiators of gene transcription. Moreover, the ability of nuclear receptors to sequentially recruit a variety of transcription factors and coregulators to target promoters and to orchestrate the whole process of gene transcription confirms their biological significance and stimulates intensive research and a high level of scientific interest in this field. In this review, we summarise current knowledge regarding the structure and function of nuclear receptors as principal regulators of gene expression. Emphasis is given to the molecular mechanisms of nuclear receptor-mediated transcriptional activation and repression including recent progress made in this area.

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Glucocorticoids mediate a variety of biological effects via binding their intracellular receptor. Ligand-bound glucocorticoid receptor (GR) translocates to the nucleus and regulates gene transcription in a DNA binding-dependent or independent manner. The predominant biological effect of glucocorticoids on peripheral T cells is immunosupression via transcriptional repression of genes induced during T cell activation. Glucocorticoids have been implicated in the inhibition of activation-induced T cell apoptosis by virtue of their down-regulation of Fas ligand (fasL) expression. It is believed that FasL, similar to other cytokines, is repressed by glucocorticoids via GR interaction with other transcription factors, interfering with their transactivation ability. Here, we show that human fasL is directly regulated by GR in a DNA binding-dependent manner. A negative GR element found at position -990 in the fasL promoter binds GR in vitro as well as in the chromatin context. This negative glucocorticoid response element overlaps with a known NFkappaB binding site. GR down-regulates fasL promoter by competing with NFkappaB for binding to the common response element. Thus, fasL is the first gene described whose repression by GR is mediated by sterical occlusion of NFkappaB DNA binding. This type of repression represents an additional mechanism for the GR-NFkappaB mutual antagonism.

BackgroundFor selection and evaluation of potential biomarkers, inclusion of already published information is of utmost importance. In spite of significant advancements in text- and data-mining techniques, the vast knowledge space of biomarkers in biomedical text has remained unexplored. Existing named entity recognition approaches are not sufficiently selective for the retrieval of biomarker information from the literature. The purpose of this study was to identify textual features that enhance the effectiveness of biomarker information retrieval for different indication areas and diverse end user perspectives.MethodsA biomarker terminology was created and further organized into six concept classes. Performance of this terminology was optimized towards balanced selectivity and specificity. The information retrieval performance using the biomarker terminology was evaluated based on various combinations of the terminology's six classes. Further validation of these results was performed on two independent corpora representing two different neurodegenerative diseases.ResultsThe current state of the biomarker terminology contains 119 entity classes supported by 1890 different synonyms. The result of information retrieval shows improved retrieval rate of informative abstracts, which is achieved by including clinical management terms and evidence of gene/protein alterations (e.g. gene/protein expression status or certain polymorphisms) in combination with disease and gene name recognition. When additional filtering through other classes (e.g. diagnostic or prognostic methods) is applied, the typical high number of unspecific search results is significantly reduced. The evaluation results suggest that this approach enables the automated identification of biomarker information in the literature. A demo version of the search engine SCAIView, including the biomarker retrieval, is made available to the public through http://www.scaiview.com/scaiview-academia.html.ConclusionsThe approach presented in this paper demonstrates that using a dedicated biomarker terminology for automated analysis of the scientific literature maybe helpful as an aid to finding biomarker information in text. Successful extraction of candidate biomarkers information from published resources can be considered as the first step towards developing novel hypotheses. These hypotheses will be valuable for the early decision-making in the drug discovery and development process.