Nuclear receptor hgands

In the case of intracellularly localized receptors the hormone must enter the cell in order to be able to interact with the receptor. The hormone usually penetrates the target cell by passive diffusion. The nuclear receptors can be classified as ligand-controlled transcription activators. The hormone acts as the activating hgand the activated receptor stimulates the transcriptional activity of genes which carry DNA elements specific for the receptor. 

Signal transduction by nuclear receptors is shown schematically in fig. 4.4. The natural hgands of nuclear receptors are lipophilic hormones that can enter the cell in a passive manner. A transmittance of the signal at the cell membrane, is not necessary, as is the case in the signaling via transmembrane receptors. Once inside the cell the hormone... 

For this group of patients, there is a requirement for a novel therapeutic approach and several are under investigation. One such area of interest is the use of retinoids, agents that are thought to act as nuclear hormone receptor hgands to restore iodine uptake in thyroid cells, i.e., causing the redifferentiation of the thyroid cells. 

PXR shares common stractural features that are characteristic of nuclear receptors [49] a DNA binding domain (DBD), hinge and hgand-bind-ing domain (LBD). Ligand-independent activation function 1 (AF-1) is shortened in PXR and... 

Inflammation is induced by the release of proinflammatory mediators from the cytosol of damaged or infected cells (Sect. 13.2.2). One of the first identified cytokines was an osteoclast activation factor later found to induce a multitude of other proinflammatory events, InterLeukin-1 (IL-1). A second was Tumor Necrosis Factor (TNF), more formally known as tumor necrosis factor-alpha, TNF-a (Sect. 13.2.2). The binding of these proteins to receptors on adjacent cells activates Nuclear Factor kappa B (NFkB), a protein in the leukocyte cytosol. The hgand-bound receptor indirectly phosphorylates an NFkB partner protein (Inhibitor of NFkB, IkB) in the cytosol. The phosphorylated IkB is targeted for destruction and its loss exposes a nuclear locahzation sequence on the NFkB protein which can now enter the nucleus where it induces the expression of important proteins, depending on the type of cell that is activated. ODAR is a Receptor Activator of Nuclear Factor kappa B (RANK), one of a large family of proinflammatory hgand receptors on leukocytes. 

For efficient gene delivery into the nucleus of target cells, the non-viral vectors must overcome several barriers, such as the plasma membrane, the endosomal membrane, and the nuclear membrane. Thus, to overcome the barriers, the non-viral gene delivery system must be equipped with various functional devices such as hgands for specific receptors, pH-sensitive fusogenic peptides for endosomal escape, and a nuclear locahzation signal (NLS) for enhanced nuclear dehvery [1]. 

These receptors mediate the effects of TNFa (TNF receptors), and of the RANK hgand, RANK-L or receptor activator of nuclear factor-kB, and its endogenous antagonist, osteoprotegerin (OPG), RANK receptors. 

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