Nuclear hormone receptors function

Ordentlich P, Downes M, Evans RM. 2001. Corepressors and nuclear hormone receptor function. Curr. Topic Microbiol. Immunol. 254 101-16... 

This chapter reviews the main characteristics of two of the better known members of the nuclear hormone receptor family estrogen receptors a and ft (ERa and ER/i). First, the different functional regions harbored by the molecule of the receptor are described. These properties will be used to describe the cellular, molecular, and other consequences that derive from the interactions of receptors with their own hormone, other proteins, or DNA. 

Melvin, V.S., Roemer, S.C., Churchill, M.E.A., and Edwards, D.P. (2002) The C-terminal extension (CTE) of the nuclear hormone receptor DNA binding domain determines interactions and functional response to the HMGB-1/-2 co-regulatory proteins. J. Biol. Chem. 277, 25115-25124. 

The farnesoid X receptor is a member of the class of nuclear hormone receptors, which have key roles in development and homeostasis, as well as in many diseases like obesity, diabetes and cancer. The farnesoid X receptor shows structural similarity to the estrogen receptor (ER ), which mediates a broad spectrum of physiological functions such as regulation of reproduction, modulation of bone density, cholesterol transport and breast cancer. The farnesoid X receptor also shows similarity with the peroxisome proliferation-activated receptor y (PPARy), which is involved in fat metabolism, inflammatory and immune responses. The estrogen receptor (ER ), the peroxisome proliferation-activated receptor y (PPARy) and the farnesoid X receptor (FXR) can be clustered in a... 

Nuclear receptors exert their different transcriptional functions through interactions with and the recruitment of co-factors to responsive promoters. Co-factors are either positive or negative regulatory proteins and are classified as co-activators, which promote, or co-repressors, which attenuate the activity of nuclear hormone receptors [46]. The molecular mechanisms that regulate the mutually exclusive interactions of the nuclear receptor with either class of co-factors have been analysed by crystallographic studies. Functional and structural studies have shown that co-activators interact with the transactivation function (AF) of nuclear hormone receptors via short, leucine-rich motifs (LXXLL) termed NR boxes , thereby transducing hormonal signals to the basal transcription machinery [47]. 

Fig. 4 Co-activator and co-repressor complexes are required for nuclear hormone receptor-mediated transcriptional regulation. The tissue-selective fine-tuning of gene transcription by nuclear hormone receptors is due to different co-regulatory complexes that have various functions and enzymatic activities. Co-activator complexes include factors that contain ATP-dependent chromatin remodelling activity often associated with histone acetyltransferase (HAT) activity. Co-repressors include ATP-dependent chromatin remodelling complexes, which function as platforms for the recruitment of several subcomplexes that often contain histone deacetylase (HDAC) activity...

Rastinejad F. Structure and function of the steroid and nuclear receptor DNA binding domain. In The Molecular Biology of Steroid and Nuclear Hormone Receptors. Ereedman LP, ed. 1998. Birkhauser, Boston, pp. 105-131. 

Figure 2 Nuclear hormone receptor structure and ligands, (a) The functional domains of nuclear hormone receptors. They act as either homodimers or heterodimers with a ligand binding domain and a DNA binding domain that are separated by a linker sequence, (b) The conformational change in helix 12 when ligand binding occurs (61, 62). All-trans retinoic acid is shown behind helix 12. (c) Examples of synthetic ligands for estrogen receptor (SERMs) and thyroid hormone receptor (Thyromimetics).

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