Mediator-related proteins

A small number of proteins, including NCoR and SMRT, comprise the corepressor family. They function, at least in part, as described in Figure 43-2. Another family includes the TRAPs, DRIPs, and ARC (Table 43-6). These so-called mediator-related proteins range in size from 80 kDa to 240 kDa and are thought to be involved in linking the nuclear receptor-coactivator complex to RNA polymerase II and the other components of the basal transcription apparatus. 

Cytokines and Immunophilins. A large number of inflammatory mediators and related proteins including the cytokines, colony stimulating factors (CSFs), interferons (IFNs), tumor necrosis factors (TNFs), growth factors (see Growth regulators), neurotrophic factors, and immunophilins are found in the mammalian CNS and appear to play a significant role in CNS function both in development and in aspects of brain homeostasis (40—43). 

Chylomicron remnants are taken up by the liver by receptor-mediated endocytosis, and the cholesteryl esters and triacylglycerols are hydrolyzed and metabolized. Uptake is mediated by a receptor specific for apo E (Figure 25-3), and both the LDL (apo B-lOO, E) receptor and the LRP (LDL receptor-related protein)... 

Pol II associates with other proteins to form a holoenzyme complex. In yeast, at least nine gene products—called Srb (for suppressor of RNA polymerase B)—bind to the CTD. The Srb proteins—or mediators, as they are also called—are essential for pol II transcription, though their exact role in this process has not been defined. Related proteins comprising even more complex forms of RNA polymerase II have been described in human cells. 

Figure 43-11. The hormone response transcription unit. The hormone response transcription unit is an assembly of DNA elements and bound proteins that interact, through protein-protein interactions, with a number of coactivator or corepressor molecules. An essential component is the hormone response element which binds the ligand (A)-bound receptor (R). Also Important are the accessory factor elements (AFEs) with bound transcription factors. More than two dozen of these accessory factors (AFs), which are often members of the nuclear receptor superfamily, have been linked to hormone effects on transcription. The AFs can interact with each other, with the liganded nuclear receptors, or with coregulators. These components communicate with the basal transcription complex through a coregulator complex that can consist of one or more members of the pi 60, corepressor, mediator-related, or CBP/p300 families (see Table 43-6).

Liu Y, Jones M, Hingtgen CM, Bu G, Laribee N, Tanzi RE, Moir RD, Nath A, He JJ (2000) Uptake of HIV-1 tat protein mediated by low-density lipoprotein receptor-related protein disrupts the neuronal metabolic balance of the receptor ligands. Nat Med 6 1380-1387... 

The delicate balance maintained by these factors is altered in patients with cancer by two principal mechanisms tumor production of humoral factors that alter calcium metabolism (humoral hypercalcemia) and local osteolytic activity from bone metastases.27 Humoral hypercalcemia causes around 80% of all hypercalcemia cases and is mediated primarily by systemic secretion of parathyroid hormone-related protein... 

Lakkaraju A, Rahman YE, Dubinsky JM. Low-density lipoprotein receptor-related protein mediates the endocytosis of anionic liposomes in neurons. J Biol Chem 2002 277(17) 15085-15092. 

Tsukiyama, T., Becker, P.B., and Wu, C. (1994) ATP-dependent nucleosome disruption at a heat-shock promoter mediated by binding of GAGA transcription factor. Nature 367, 525-532. Laurent, B.C., Yang, X., and Carlson, M. (1992) An essential Saccharomyces cerevisiae gene homologous to SNF2 encodes a helicase-related protein in a new family. Mol. Cell Biol. 12, 1893-1902. 

The rationale for this type of contrast agent is to use the endogenous metabolic pathway of lipid metabolism in the liver for the transport of iodinated substances. Chylomicron remnants are naturally occurring lipoproteins in the blood that are responsible for the transport of lipids into the liver. Three different mechanisms for this transport are discussed direct uptake by the low-density lipoprotein receptor transport to the low-density lipoprotein receptor-related protein (LRP) mediated by heparan sulfate proteoglycan (HSPG) or direct HSPG-LRP uptake and direct HSPG uptake. One of the prerequisites for particles to be transported by these mechanisms is a mean diameter of less than 100-300 run. 

The LDL receptor also binds to apoE and plays a significant role in the hepatic uptake of chylomicrons and VLDL remnants. However, if LDL receptors are unavailable (as, for example, in a mouse strain that lacks the gene for the LDL receptor), VLDL remnants and chylomicrons are still taken up by the liver even though LDL is not. This indicates the presence of a back-up system for receptor-mediated endocytosis of VLDL remnants and chylomicrons. One back-up receptor is lipoprotein receptor-related protein (LRP), which binds to apoE as well as to a number of other ligands. 

NMDA receptors are clustered at postsynaptic sites where cytoplasmic adapter proteins anchor them to the cytoskeleton. Some adapter proteins contain a PDZ domain while others lack this. The PDZ domain is a protein-protein interaction motif of approximately 90 amino acids, which in most cases, binds their target proteins at the C-terminus ends. For example a PDZ domain protein, PSD-95, interacts with the C-terminus of the NR2 subunit. Its interaction with tubulin-based cytoskele-tal protein is mediated by a novel postsynaptic protein called CRIPT (Niethammer et al., 1998). Thus NR1 and NR2 subunits and their related proteins are crucial for efficient gating of NMDA receptor channels. 

R.C. Kowal, J. Herz, J.L. Goldstein, V. Esser and M.S. Brown, Low density lipoprotein receptor related protein mediates uptake of cholesteryl esters derived from apoprotein E-enriched lipoproteins, Proc. Natl. Acad. Sci. USA 86 (1989) 5810-5814. 

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