The Arabidopsis thaliana response regulator 4, expressed in response to phytochrome B action, specifically interacts with the extreme amino-terminus of the photoreceptor. The response regulator 4 stabilizes the active Pfr form of phytochrome B in yeast and in planta, thus elevates the level of the active photoreceptor in vivo. Accordingly, transgenic Arabidopsis plants overexpressing the response regulator 4 display hypersensitivity to red light but not to light of other wavelengths. We propose that the response regulator 4 acts as an output element of a two-component system that modulates red light signaling on the level of the phytochrome B photoreceptor.
Hormones are important regulators of plant growth and development. In Arabidopsis, perception of the phytohormones ethylene and cytokinin is accomplished by a family of sensor histidine kinases including ethylene-resistant (ETR) 1 and cytokinin-response (CRE) 1. We identified the Arabidopsis response regulator 2 (ARR2) as a signalling component functioning downstream of ETR1 in ethylene signal transduction. Analyses of loss-of-function and ARR2-overexpressing lines as well as functional assays in protoplasts indicate an important role of ARR2 in mediating ethylene responses. Additional investigations indicate that an ETR1-initiated phosphorelay regulates the transcription factor activity of ARR2. This mechanism may create a novel signal transfer from endoplasmic reticulumassociated ETR1 to the nucleus for the regulation of ethylene-response genes. Furthermore, global expression profiling revealed a complex ARR2-involving two-component network that interferes with a multitude of different signalling pathways and thereby contributes to the highly integrated signal processing machinery in higher plants.
Granzymes (Gzm) are a group of serine proteases which are stored in the granules of cytotoxic lymphocytes. In humans, five granzymes have been characterized to date at the molecular level. While GzmA and GzmB have been extensively studied, little is known about GzmH, GzmK and GzmM. In this study, we describe the generation of mAbs against human GzmK and GzmM by genetic immunization. The obtained anti-GzmK and anti-GzmM mAbs are not cross-reactive with GzmA, GzmB, GzmM and GzmA, GzmB, GzmK, respectively, and show a granular staining pattern in human lymphocytes. Flow cytometric analysis of peripheral blood lymphocytes revealed that GzmA, GzmM and perforin show a similar distribution. They are expressed in almost all CD16+CD56+ NK cells, CD3+CD56+ NKT cells and gammadelta T cells as well as in 20-30% of all CD3+CD8+ TC cells. Surprisingly, GzmK was not detected in the highly cytotoxic CD16+CD56+ NK cells but was preferentially expressed in lymphocytes of the T cell lineage, staining 20% of CD3+CD8+ TC cells, 50% of CD3+CD56+ NKT cells and 40% of gammadelta T cells, as well as 60% of the small sub-population of CD56bright+ NK cells. Our data suggest that human granzymes are differentially expressed in distinct sub-populations of peripheral blood lymphocytes.
The inducible two‐component signal transduction mechanism typically involves two common signaling molecules. First, a sensor kinase that consists of a signal‐sensing input domain physically coupled to a transmitter module and, second, a response regulator that contains a receiver module and a signal‐output domain. Such sensor kinase/response regulator pairs trigger a variety of cellular activities in response to environmental stimuli. Recently, several components of this signaling mechanism including sensor kinases and response regulators have been identified in eukaryotes, including plants. Here, we describe a new subclass of eukaryotic Arabidopsis response regulator‐like protein (ARLP) genes that are differentially expressed in plant tissues. The receiver modules of the encoded proteins contain the amino acid residues conserved in all response regulators and have a predicted response regulator‐like secondary structure. These novel ARLPs are localized in the nucleus, are transcriptionally active in yeast when fused to the heterologous Gal4 DNA‐binding domain and, within their output domains, show structural homology to basic helix‐loop‐helix (bHLH) transcription factors. These results strongly suggest that response regulators with transcription factor properties exist in higher plants.
Unfractionated heparin (UFH), the standard anticoagulant for cardiopulmonary bypass (CPB) surgery, carries a risk of post-operative bleeding and is potentially harmful in patients with heparin-induced thrombocytopenia-associated antibodies. To improve the activity of an alternative anticoagulant, the RNA aptamer 11F7t, we solved X-ray crystal structures of the aptamer bound to factor Xa (FXa). The finding that 11F7t did not bind the catalytic site suggested that it could complement small-molecule FXa inhibitors. We demonstrate that combinations of 11F7t and catalytic-site FXa inhibitors enhance anticoagulation in purified reaction mixtures and plasma. Aptamer-drug combinations prevented clot formation as effectively as UFH in human blood circulated in an extracorporeal oxygenator circuit that mimicked CPB, while avoiding side effects of UFH. An antidote could promptly neutralize the anticoagulant effects of both FXa inhibitors. Our results suggest that drugs and aptamers with shared targets can be combined to exert more specific and potent effects than either agent alone.
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