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Translocation "Activated" of cytoplasmic receptor complex

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FIGURE 1-41 Model of steroid hormone mode of action. A detailed description is given in the text.

mRNA Translation mRNA

FIGURE 1-41 Model of steroid hormone mode of action. A detailed description is given in the text.

cytoplasmic activated receptor translocates to the nucleus, probably through a nucleopore. Then in step 6, the activated receptor, or more likely a homodimer of the receptor, seeks out the correct sequence of DNA that will allow it to form a high-affinity complex between the receptor and the hormone response elements (HRE) of the promoters of a selected set of genes and also any required transcription factors. As a consequence of the activated receptor binding to the promoters, either induction or repression of that gene will occur, leading to more or less of the mRNA coded for by that gene. The newly transcribed mRNAs are translocated to the cytoplasm where they become incorporated into polysomes and undergo translation (step 7). In the final step 8, the increased or decreased amount of new proteins generates more or less of the biological response(s) dictated by that hormone in that target cell. For any given hormone, an incredible array of biological responses can be modulated depending upon the phenotype of the target cell that possesses the cognate receptor. In any given target cell phenotype, only a small subset of genes will have their DNA chromatin in an active or "open" configuration. Thus, while a hormone may modulate as many as 300 genes in a given organism, in a specific target cell perhaps only a few genes will be available for regulation.

Consensus DNA sequences, known as hormone response elements (HRE), which precisely define the specific acceptor sites for the steroid hormone receptors, are now known; see Table 1-10.

On the basis of the regions of maximum sequence homology, the steroid receptors may be classified into two subfamilies: one including the glucocorticoid, progesterone, androgen, and mineralocorticoid receptors and the other group comprising the receptors for estrogen, thyroid hormone, retinoic acid, and l,25(OH)2D3. The primary difference between the two subfamilies is the presence of two discriminatory amino acids in the knuckle region of the first zinc finger, while members within a subfamily are distinguished by the presence of unique amino acids in the stem of the second zinc finger. Also within the same subfamily, the TR and VDR appear to share strong homology in most of the functional domains defined so far, which may reflect their close evolutionary relationship. It is speculated that the human VDR, which is smaller than the TR by 75 amino acids, may have evolved prior to the TR and perhaps gave rise to the latter by gene duplication. The model of a steroid hormone receptor is presented in Figure 1-26. In the center of the molecule is the DNA-binding domain. Surprisingly, among all the members of this superfamily of proteins, there is a 60-95% amino acid homology; in spite of this sequence similarity,

TABLE 1-10 Hormone Response Elements (HRE) for Subgroups of the Steroid Hormone Receptor Superfamily"

Critical amino acids for HRE specificity

TABLE 1-10 Hormone Response Elements (HRE) for Subgroups of the Steroid Hormone Receptor Superfamily"

Critical amino acids for HRE specificity

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