Mapping of the human and other eukaryotic genomes has provided the pharmacological industry with excellent models for drug discovery. Control of cell proliferation, differentiation, activation and ...cell removal is crucial for the development and existence of multicellular organisms. Each cell cycle progression, with sequences of DNA replication, mitosis, and cell division, is a tightly controlled and complicated process that, when deregulated, may become dangerous not only to a single cell, but also to the whole organism. Regulation and the proper control of the cell cycle and of programmed cell death (apoptosis) is therefore essential for mammalian development and the homeostasis of the immune system. The molecular networks that regulate these processes are critical targets for drug development, gene therapy, and metabolic engineering. In addition to the primary, intracellular apoptotic suicide machinery, components of the immune system can detect and remove cells and tissue fragments that no longer serve their defined functions. In this review we will focus on apoptotic pathways converging on caspase family proteases, summarizing pharmacological attempts that target genes, proteins, and intermolecular interactions capable of modulating apoptosis and the inflammatory response. The upcoming pharmacological development for treatment of acute pathologies, such as sepsis, SIRS, stroke, traumatic brain injury, myocardial infarction, spinal cord injury, acute liver failure, as well as chronic disorders such as Huntington's disease, Parkinson's disease, ALS, and rheumatoid arthritis, will be discussed in details. We also suggest new potential molecular targets that may prove to be effective in controlling apoptosis and the immune response in vivo.
•Transformative approaches will be needed to address adaptation to global change.•Transformative approaches require new ways to make decisions about adaptation.•The TARA approach (Transformative ...Adaptation Research Alliance) does this.
Transformative adaptation will be increasingly important to effectively address the impacts of climate change and other global drivers on social-ecological systems. Enabling transformative adaptation requires new ways to evaluate and adaptively manage trade-offs between maintaining desirable aspects of current social-ecological systems and adapting to major biophysical changes to those systems. We outline such an approach, based on three elements developed by the Transformative Adaptation Research Alliance (TARA): (1) the benefits of adaptation services; that sub-set of ecosystem services that help people adapt to environmental change; (2) The values-rules-knowledge perspective (vrk) for identifying those aspects of societal decision-making contexts that enable or constrain adaptation and (3) the adaptation pathways approach for implementing adaptation, that builds on and integrates adaptation services and the vrk perspective. Together, these elements provide a future-oriented approach to evaluation and use of ecosystem services, a dynamic, grounded understanding of governance and decision-making and a logical, sequential approach that connects decisions over time. The TARA approach represents a means for achieving changes in institutions and governance needed to support transformative adaptation.
The two migration inhibitory factor- (MIF)-related protein-8 (MRP8; S100A8) and MRP14 (S100A9) are two calcium-binding proteins of the S100 family. These proteins are expressed during myeloid ...differentiation, are abundant in granulocytes and monocytes, and form a heterodimeric complex in a Ca
2+-dependent manner. Phagocytes expressing MRP8 and MRP14 belong to the early infiltrating cells and dominate acute inflammatory lesions. In addition, elevated serum levels of MRP8 and MRP14 have been found in patients suffering from a number of inflammatory disorders including cystic fibrosis, rheumatoid arthritis, and chronic bronchitis, suggesting conceivable extracellular roles for these proteins. Although a number of possible functions for MRP8/14 have been proposed, the biological function still remains unclear. This review addresses recent developments regarding the MRP14-mediated promotion of leukocyte-endothelial cell-interactions and the characterization of MRP8/14 heterodimers as a fatty acid binding protein complex. In view of the current knowledge, the authors will hypothesize that MRP8 and MRP14 play an important role in leukocyte trafficking, but do not affect neutrophil effector functions.
Protein complexes formed by S100A8 and S100A9 represent the only AAbinding capacity in the human neutrophilic cytosol and are involved in the intracellular arachidonic acid metabolism. The formation ...of S100A8/A9 protein complexes and the binding of calcium to the complexes are prerequisites for the specific binding of polyunsaturated fatty acids. The present study was undertaken to characterize the fatty acid binding site within the protein complex. Deletions at both termini and point mutations of different basic amino acids especially within the extended Cterminal tail of human S100A9 were introduced. The S100A9 mutant proteins were then analyzed with respect to proteinprotein interaction (GST pull downassay and yeast twohybrid system) and functional properties (arachidonic acid and calcium binding). The data give strong evidence that the unique Ctail of S100A9 containing the three consecutive histidine residues (His103-His105) represents the region to which the fatty acid carboxygroup is bound to the protein complex. The localization of the AAbinding site within the unique Ctail of S100A9 correlates with the fact that fatty acid binding has not yet been reported for other S100 proteins.
Recently, we identified the two myeloid related protein-8 (MRP8) (S100A8) and MRP14 (S100A9) as fatty acid-binding proteins (Klempt, M., Melkonyan, H., Nacken, W., Wiesmann, D., Holtkemper, U., and ...Sorg, C. (1997) FEBS Lett. 408, 81–84). Here we present data that the S100A8/A9 protein complex represents the exclusive arachidonic acid-binding proteins in human neutrophils. Binding and competition studies revealed evidence that (i) fatty acid binding was dependent on the calcium concentration; (ii) fatty acid binding was specific for the protein complex formed by S100A8 and S100A9, whereas the individual components were unable to bind fatty acids; (iii) exclusively polyunsaturated fatty acids were bound by S100A8/A9, whereas saturated (palmitic acid, stearic acid) and monounsaturated fatty acids (oleic acid) as well as arachidonic acid-derived eicosanoids (15-hydroxyeicosatetraenoic acid, prosta- glandin E2, thromboxane B2, leukotriene B4) were poor competitors. Stimulation of neutrophil-like HL-60 cells with phorbol 12-myristate 13-acetate led to the secretion of S100A8/A9 protein complex, which carried the released arachidonic acid. When elevation of intracellular calcium level was induced by A23187, release of arachidonic acid occurred without secretion of S100A8/A9. In view of the unusual abundance in neutrophilic cytosol (approximately 40% of cytosolic protein) our findings assign an important role for S100A8/A9 as mediator between calcium signaling and arachidonic acid effects. Further investigations have to explore the exact function of the S100A8/A9-arachidonic acid complex both inside and outside of neutrophils.
EF‐hand proteins are known to translocate to membranes, suggesting that they are involved in signaling events located in the cell membrane. Many proteins involved in signaling events associate ...cholesterol rich membrane domains, so called lipid rafts, which serve as platforms for controlled protein–protein interaction. Here, we demonstrate that the myeloid expressed EF‐hand proteins can be distinguished into three classes with respect to their membrane association. Grancalcin, a myeloid expressed penta EF‐hand protein, is constitutively located in lipid rafts. S100A9 (MRP14) and S100A8 (MRP8) are translocated into detergent resistant lipid structures only after calcium activation of the neutrophils. However, the S100A9/A8 membrane association is cholesterol and sphingolipid independent. On the other hand, the association of S100A12 (EN‐RAGE) and S100A6 (calcyclin) with membranes is detergent sensitive. These diverse affinities to lipid structures of the myeloid expressed EF‐hand proteins most likely reflect their different functions in neutrophils.
Additional homology searches of all Jackson laboratory murine databases 13, using human S100A12 as the query, were futile. ...a region homologous to the first exon of S100A12 is also present on the ...corresponding chromosome 2 of rat, however, exons 2 and 3 are again missing, suggesting that the S100A12 gene might be damaged in all rodents. ...several proinflammatory properties of this protein might be caused by its binding to RAGE 3. ...the RAGE-S100A12 interaction represents an attractive model to explain how RAGE and its proinflammatory ligand contribute to the pathophysiology of several inflammatory diseases 1,3.
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