/ NFAT, a transcription factor
liver enhancer sequence promoter no transcription
Figure 6.15. Tissue-specific transcription.
in the cytosol and is inactive because it is complexed to two molecules of an inhibitor protein known as Hsp90. However, when the glucocorticoid hormone enters the cell and binds to its receptor, the Hsp90 protein is displaced. The targeting sequence (page 215) that targets the receptor to the nucleus is uncovered, and the glucocorticoid receptor-hormone complex can now move into the nucleus. Here, two molecules of the complex bind to a plasma membrane cytoplasm receptor hormone complex - inhibitory protein released - targeting sequence exposed inhibitory protein nucleus glucocorticoid -1
hormone receptor |
glucocorticoid hormone inhibitory protein (hsp 90)
receptor protein is now able to bind to DNA
receptor protein is now able to bind to DNA
transcription follows mRNA
Figure 6.16. The steroid hormone receptor acts to increase gene transcription in the presence of hormone.
15-bp sequence known as the hormone response element (HRE) that lies upstream of the TATA box. The HRE is an enhancer sequence. The glucocorticoid receptor-hormone complex interacts with the preinitiation complex bound to the TATA box, and the rate at which RNA polymerase transcribes genes containing the HRE is increased.
Figure 6.17 shows why the glucorticoid hormone receptor binds to DNA as a dimer. The HRE is a palindrome—the sequence on both the top and bottom strands is the same when read in the 5' to 3' direction. Each strand of the HRE has the 6-bp sequence 5' AGAACA 3' that is known as the core recognition motif. This is the sequence to which a single receptor molecule binds. Because the HRE contains two recognition motifs, it binds two molecules of glucocorticoid receptor. The two 6-bp sequences are separated by 3 base pairs, which presumably are there to provide sufficient space for the receptor homodimer to fit snugly on the double helix. The glucocorticoid receptor is unaffected by the identity of these three base pairs, so the nucleotides are simply indicated as N in Fig. 6.17.
Chemicals that are released from one cell and that alter the behavior of other cells are called transmitters. Glucocorticoids are an example of transmitters that alter gene transcription. The cells of multicellular organisms turn the transcription of genes on and off in response to many extracellular chemicals. Unlike steroid hormones, most of these transmitters cannot enter the cell and must activate intracellular messenger systems inside the cell that in turn carry the signal onward from the plasma membrane to the nucleus (Chapter 16).
Glucocorticoid Hormones Can Repress Transcription: Rheumatoid Arthritis
Glucocorticoid treatment has been shown to give some relief to individuals who suffer from the debilitating disorder rheumatoid arthritis. Collagenase, an enzyme that digests collagen, is generated in the joints of these patients, causing destruction of the extracellular matrix and therefore chronic inflammation. Transcription of the collagenase gene is controlled by an enhancer sequence called the API site. For transcription to occur, the enhancer must be occupied by a transcription factor called API, which, like the active glucocorticoid receptor, is a dimer. Glucocorticoid hormones inhibit transcription of the collagenase gene by an ingenious mechanism. The glucocorticoid hormone, on entering the cell interacts with the glucocorticoid receptor as shown in Figure 6.16. The receptor-hormone complex moves to the nucleus and binds to the proteins that would otherwise dimerize to form API. The heterodimer is unable to activate transcription of the collagenase gene. By depleting the pool of API subunits, the glucocorticoid receptor-hormone complex prevents transcription of the collagenase gene.
Medical St. John's Wort and the Pill Relevance When we ingest plant products and other chemicals foreign to us, the body re-6.1 sponds by increasing the amounts of a group of proteins known as the cytochromes P450 (CYPs). This remarkable response, found largely in the liver, is our built-in detoxication system. The foreign chemical signals the appropriate CYP gene to activate, transcription takes place, and more CYP protein is produced. The CYP protein then metabolizes the foreign chemical so that it will be cleared from the body quickly and efficiently through the urine or feces. To the liver, a medicinal drug is just another foreign chemical, and the cytochrome P450 system is used to destroy it.
St. John's wort is a herbal remedy, taken by many as a natural antidepressant. One of the active components is the chemical hyperforin, which has been shown to decrease the effectiveness of several therapeutic drugs including the oral contraceptive pill, the HIV protease inhibitor indinavir, and immunosuppressants such as cyclosporin. This is because each of these drugs is metabolized by a cytochrome P450 called CYP3A4, and the gene for CYP3A4 is activated by hyperforin. Because the activation of the CYP3A4 gene results in more CYP3A4 protein, the prescribed drug, in a person also taking St. John's wort, is metabolized more rapidly, cleared from the body quickly, and is therefore less effective.
The transcription of the CYP3A4 gene is increased because hyperforin passes to the nucleus and binds to a receptor called the pregnane X receptor (PXR). The receptor-hyperforin complex is then able to dimerize with another receptor called RXR. The dimer binds to an enhancer sequence of the CYP3A4 gene, interacts with the transcription preinitiation complex, and triggers RNA polymerase II to begin transcription of CYP3A4 mRNA.
This activation of the CYP3A4 gene by St. John's wort means that this herbal remedy should be taken with caution if a patient has been prescribed a therapeutic drug. CYP3A4 is responsible for the metabolism of about 80% of currently prescribed drugs.
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