These results provide strong evidence that oxidative stress is significantly involved in cartilage degradation in experimental arthritis, and indicate that the presence of a functional Nrf2 gene is a major requirement for limiting cartilage destruction.
Objective-Synthesis and maturation of G protein-coupled receptors are complex events that require an intricate combination of processes including protein folding, posttranslational modifications, and transport through distinct cellular compartments. Little is known concerning the regulation of G protein-coupled receptor transport from the endoplasmic reticulum to the cell surface. Methods and Results-Here we show that the cytoplasmatic carboxy-terminal of the angiotensin AT2 receptor (AT2R) acts independently as an endoplasmic reticulum-export signal. Using a yeast two-hybrid system, we identified a Golgi membrane-associated protein termed ATBP50 (for AT2R binding protein of 50 kDa) that binds to this motif. We also cloned ATBP60 and ATBP135 encoded by the same gene as ATBP50 that mapped to chromosomes 8p21.3. Downregulation of ATBP50 using siRNA leads to retention of AT2R in inner compartments, reduced cell surface expression, and decreased antiproliferative effects of the receptor. Conclusion-Our results indicate that ATBP50 regulates the transport of the AT2R to cell membrane by binding to a specific motif within its cytoplasmic carboxy-terminal and thereby enabling the antiproliferative effects of the receptor. T he heptahelical G protein-coupled receptors (GPCRs) represent one of the largest protein families in eukaryotic cells. 1 A large number of structure-function studies have defined receptor sequences that are essential for ligand binding, G protein coupling, and desensitization. In contrast, little is known concerning the requirements for the transport of these proteins to the plasma membrane. Intracellular accessory proteins can be critical for GPCR biogenesis, including aspects of receptor trafficking. Recent discoveries have identified multiple membrane-associated proteins that dictate the delivery of the receptor to the cell surface. 2 See page 15The octapeptide hormone angiotensin II (Ang II) exerts a wide variety of physiological actions such as vasoconstriction and aldosterone secretion, but it is also involved in pathological mechanisms of atherosclerosis as well as vascular and cardiac growth. Ang II mainly interacts with two receptor subtypes, designated AT1 and AT2 receptor (AT1R, AT2R), both belonging to the superfamily of GPCRs. The majority of its well-described effects are mediated by the AT1R. 3 Increasing evidence indicates, however, that the AT2R subtype can modulate the effects of AT1R, including those on blood pressure, 4 -8 cardiac and vascular cell growth, 9 -11 and tissue regeneration after injury. [12][13][14][15] Thus, it has been shown that stimulation or overexpression of AT2R in certain cell lines inhibits cell proliferation induced by growth factors 16,17 and promotes neuronal differentiation 18 -21 as well as apoptosis. [22][23][24][25] The growth inhibitory effects of the AT2R have been shown to be associated with the activation and/or induction of a series of phosphatases including the protein tyrosine phosphatase SHP-1, mitogenactivated protein kinase phosphatase-1 (MK...
The transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) is a major regulator of oxidative stress defence in the human body. As Nrf2 regulates the expression of a large battery of cytoprotective genes, it plays a crucial role in the prevention of degenerative disease in multiple organs. Thus it has been the focus of research as a pharmacological target that could be used for prevention and treatment of chronic diseases such as multiple sclerosis, chronic kidney disease or cardiovascular diseases. The present review summarizes promising findings from basic research and shows which Nrf2-targeting therapies are currently being investigated in clinical trials and which agents have already entered clinical practice.
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