As discussed in section 9.1.1, there is continual turnover of proteins in the cell, and not all proteins are broken down and replaced at the same rate. Some are relatively stable, whereas others, and especially enzymes that are important in metabolic regulation, have short half-lives — of the order of minutes or hours. This rapid turnover means that it is possible to control metabolic pathways by changing the rate at which a key enzyme is synthesized, and hence the total amount of that enzyme in the tissue. An increase in the rate of synthesis of an enzyme is induction, while the reverse, a decrease in the rate of synthesis of the enzyme by a metabolite, is repression. A number of key enzymes in metabolic pathways are induced by their substrates, and similarly many are repressed by high concentrations of the end-products of the pathways they control.
Slow-acting hormones, including the steroid hormones such as cortisol and the sex steroids (androgens, oestrogens and progesterone), vitamin A (section 22.214.171.124), vitamin D (section 11.3.3) and the thyroid hormones (section 126.96.36.199) act by changing the rate at which the genes for individual enzymes are expressed.
The response is considerably slower than for hormones that increase the activity of existing enzyme molecules because of the need for an adequate amount of new enzyme protein to be synthesized. Similarly, the response is prolonged, as after the hormone has ceased to act there is still an increased amount of enzyme protein in the cell, and the effect will only diminish as the newly synthesized enzyme is catabolized. The time scale of action of slow-acting hormones ranges from hours to days.
As shown in Figure 10.10, the hormone enters the cell and binds to a receptor protein in the nucleus. Binding of the hormone causes a conformational change in the receptor protein and loss of a chaperone protein that is bound to the unoccupied receptor. Loss of the chaperone protein reveals a dimerization site on the receptor. The hormone—receptor complex dimerizes and undergoes activation that enables it to bind to a hormone response element on DNA, which may be some distance upstream of the gene that is regulated.
Binding of the activated hormone—receptor complex to the hormone response element acts as a signal to recruit the various transcription factors required for hormone enters cell and binds to receptor protein occupied receptor undergoes conformational change occupied receptor dimerizes occupied receptor dimerizes
Figure 10.10 The action of steroid hormones.
receptor dimer binds to hormone response element on DNA, enhancing transcription
transcription of the gene, leading to increased synthesis of mRNA (section 188.8.131.52). Increased mRNA synthesis results in increased synthesis of the protein (section 9.2.3).
A cell will only respond to a slow-acting hormone if it synthesizes the receptor protein. The response to the same hormone in different tissues, and at different stages in development, may well be different, because only genes that are expressed in the cell will be induced. The control of gene expression by slow-acting hormones is not a matter of switching on a gene that is otherwise silent. Rather, the hormone causes an increase in the expression of a gene which is in any case being transcribed at a low rate. Similarly, the secretion of steroid hormones is not a strictly on/off affair, rather a matter of changes in the amount being secreted.
Although there is a great deal of information about the molecular mechanisms involved in initiating the responses to nuclear-acting hormones, less is known about the termination of action. It is known that vitamin B6 (section 11.9.2) displaces hormone—receptor complexes from DNA binding, and there is good evidence that the responsiveness of target tissues to slow-acting hormones is increased in vitamin B6 deficiency. As hormone stimulation decreases, so the newly synthesized enzymes are catabolized, as discussed in section 184.108.40.206.
The amplification of the hormone signal in response to a slow-acting hormone is the result of increased synthesis of mRNA — there is increased transcription for as long as the hormone—receptor complex remains bound to the hormone response element on DNA. Each molecule of mRNA is translated many times over, leading to a considerable (albeit relatively slow) increase in the amount of enzyme protein in the cell. Each molecule of enzyme will then catalyse the metabolism of many thousands of mol of substrate per second, until it is catabolized.
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