C. elegans. Some mammalian nuclear receptors are regulated by intracellular metabolites rather than by secreted signal molecules; the peroxisome proliferation-activated receptors (PPARs), for example, bind intracellular lipid metabolites and regulate the transcription of genes involved in lipid metabolism and fat-cell differentiation. It seems likely that the nuclear receptors for hormones evolved from such receptors for intracellular metabolites, which would help explain their intracellular location.
Steroid hormones—which include cortisol, the steroid sex hormones, vitamin D (in vertebrates), and the molting hormone ecdysone (in insects)—are all made from cholesterol. Cortisol is produced in the cortex of the adrenal glands and influences the metabolism of many types of cells. The steroid sex hormones are made in the testes and ovaries and are responsible for the secondary sex characteristics that distinguish males from females. Vitamin D is synthesized in the skin in response to sunlight; after it has been converted to its active form in the liver or kidneys, it regulates Ca2+ metabolism, promoting Ca2+ uptake in the gut and reducing its excretion in the kidneys. The thyroid hormones, which are made from the amino acid tyrosine, act to increase the metabolic rate of many cell types, while the retinoids, such as retinoic acid, are made from vitamin A and have important roles as local mediators in vertebrate development. Although all of these signal molecules are relatively insoluble in water, they are made soluble for transport in the bloodstream and other extracellular fluids by binding to specific carrier proteins, from which they dissociate before entering a target cell (see Figure 15–3B).
The nuclear receptors bind to specific DNA sequences adjacent to the genes that the ligand regulates. Some of the receptors, such as those for cortisol, are located primarily in the cytosol and enter the nucleus only after ligand binding; others, such as the thyroid and retinoid receptors, are bound to DNA in the nucleus even in the absence of ligand. In either case, the inactive receptors are usually bound to inhibitory protein complexes. Ligand binding alters the conformation of the receptor protein, causing the inhibitory complex to dissociate, while also causing the receptor to bind coactivator proteins that stimulate gene transcription (Figure 15–65). In other cases, however, ligand binding to a nuclear receptor inhibits transcription: some thyroid hormone receptors, for example, act as transcriptional activators in the absence of their hormone and become transcriptional repressors when hormone binds.
Thus far, we have focused on the control of gene expression by extracellular signal molecules produced by other cells. We now turn to gene regulation by a more global environmental signal: the cycle of light and darkness that results from the Earth’s rotation.
Life on Earth evolved in the presence of a daily cycle of day and night, and many present-day organisms (ranging from archaea to plants and humans) possess an internal rhythm that dictates different behaviors at different times of day. These behaviors range from the cyclical change in metabolic enzyme activities of a bacterium to the elaborate sleep–wake cycles of humans. The internal oscillators that control such diurnal rhythms are called circadian clocks.
Having a circadian clock enables an organism to anticipate the regular daily changes in its environment and take appropriate action in advance. Of course, the internal clock cannot be perfectly accurate, and so it must be capable of being reset by external cues such as the light of day. Thus, circadian clocks keep running
Figure 15–64 Some signal molecules that bind to intracellular receptors. Note that all of them are small and hydrophobic. The active, hydroxylated form of vitamin D3 is shown. Estradiol and testosterone are steroid sex hormones.