Nuclear steroid hormone receptors

Both the HLH motif and Zn2+(Cys)4 motifs are found in the DNA-binding domain (DBD) of nuclear steroid-hormone receptors (see Chapter 11). 

The intracellular distribution of steroid hormone receptors has long been the object of controversy. The first theoretical formulation on the intracellular location of the ERs was elaborated by Jensen in 1968 and is known as the two-step theory. Its execution was based entirely on biochemical observations obtained by means of tritium-marked estradiol. The ERs, in cells not exposed to hormones, are found abundantly in the soluble cell fraction, or cytosol (Fig. 1.1). Treatment with hormones confines the receptors to the particulated or nuclear fraction and causes their disappearance from the cytosol. The two-step theory established that the receptor is found in the cytoplasm naturally and upon the arrival of a hormone it is transformed into a complex hormone-receptor (first step) capable of translocating itself to the nucleus and of modifying gene expression (second step). 

Direct repeat of the recognition sequence requires a nonsymmetrical spatial arrangement of the bound protein subunits (see chapter 4, Nuclear Receptors). The protein-DNA complex has, in this case, a polar character and the protein bound on each of the two halves of the recognition element can carry out different functions. Direct 2-fold repeats are commonly observed for the DNA-binding elements of the steroid hormone receptors (see chapter 4). 

Extensive deletion and mutation studies, as well as sequence comparisons, have shown that the nuclear receptors are constructed modularly. At the level of the primary structure the steroid hormone receptors can be divided into five different domains (fig. 4.5), each with specific functions. 

The steroid hormone receptors are sequence specific DNA binding proteins whose cognate DNA elements are termed hormone responsive elements" (HREs). The HREs known to date possess a common structure. They are composed primarily of two copies of a hexamer sequence. In table 4.1 are listed the hexamer sequences of the HREs of important nuclear receptors. 

The steroid hormone receptors can not only activate transcription, but can also repress transcription (review Beato, 1995). This function is mechanistically poorly understood. Repression by nuclear receptors has been observed for genes whose control regions have, apart from the HREs, binding sites for other transcription factors, e.g. AP-1 and NFxB. In AP-1 and NFxB controlled genes it has been observed that the steroid hormone receptors have an inhibitory effect on the transcription activation of both transcription factors. The mechanism of this mutual interaction remains unclear. 

The steroid hormone receptors are phophoproteins which are usually phosphorylated on several positions. The phosphorylation sites are mainly foimd in the N-terminal region of the receptors. Serine phosphorylation prevails. One rare example of tyrosine phosphorylation is described for the case of estrogen receptors. The consequences of phosphorylation for the receptor proteins are varied. It is conceivable, and in some cases experimentally proven, that it has influence on hormone binding, nuclear transport, DNA binding and transactivation. 

Like other nuclear receptors (e.g., steroid hormone receptors, thyroid hormone receptors) the PPARs function as ligand-activated transcription factors. As illustrated in Fig. 1 (see color insert) individual PPARs function as dimers with members of the retinoid X receptor (RXR) family (23). Evidence for an interaction of PPARs with RXRs includes co-expression studies that were performed with yeast lacking endogenous nuclear receptors (24). 

The nuclear vitamin D receptor was originally studied in intestinal mucosa, hut has subsequently been found in a variety of other tissues that have therefore been shown to be vitamin D-responsive, including kidneys, bone, parathyroid gland, -islet cells of the pancreas, pituitary, placenta, uterus, mammary glands, skin, thymus, monocytes, macrophages, and activated T lymphocytes. Like other steroid hormone receptors, it is a zinc finger protein it has the same high affinity (of the order of 10 " M) for both calcitriol and ercalcitriol. 

In Table 11.2 the properties of two families of nuclear receptors, A and B, are compared. To family A belong the steroid hormone receptors and to family B, the non-steroidal receptors,25 the thyroid hormone receptors, the retinoic acid receptors, the vitamin D3 receptor, the peroxysome proliferator activating receptor, and several orphan receptors. 

Table 11.2 The two families of nuclear receptors and their properties are compared. Group A are the steroid hormone receptors and group B the non-steroidal nuclear receptors...

Nuclear receptors. Intracellular DNA-binding proteins which bind lipophilic ligands which pass the membrane without assistance. Examples are the steroid hormone receptors and the receptors for non-steroidal ligands, such as retinoids and the hormone thyroxin. 

McKay LI, Cidlowski JA. Cross-talk between nuclear factor-kappaB and the steroid hormone receptors mechanisms of mutual antagonism. Mol. Endo. 1998 12 45-56. 

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