Specific Example of Steroid Hormone Action at Cell Level Programmed Death

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chromatin, probably as a dimer, presumably in search of the specific response element (Table 21.4). Thus these receptors are transacting factors and may act in concert with other transacting factors to provide the appropriate structure to initiate transcription. Most steroid receptors have in their DNA­binding domains an SV40­like sequence (i.e., Pro­Lys­Lys­Lys­Arg­Lys­Val) known to code for nuclear translocation. Steroid receptors have variants of this sequence; some degeneracy is permitted but probably a specific lysine residue cannot be altered. This signal may provide recognition for the nucleopore.
Figure 21.20 Hypothetical minimal model of a non­DNA­binding form of a steroid receptor. This form of the receptor cannot bind to DNA because the DNA­binding site is blocked by the 90­kDa hsp proteins or by some other constituent. Mass of this complex is approximately 300 kDa.
Steroid Receptors Can Be Upregulated or Downregulated Depending on Exposure to the Hormone
In general, many membrane or intracellular receptors are downregulated when the cell has been exposed to a certain amount of the hormonal ligand. In some cases, the downregulation is called "desensitization." Downregulation can take many forms. For membrane receptors the mechanism may be internalization by endocytosis of the receptors after exposure to hormone (see p.876). Internalization reduces the number of receptors on the cell surface and renders the cell less responsive to hormone; that is, desensitizes the cell. In the case of intracellular steroid receptors, downregulation generally takes the form of reducing the level of receptor mRNA, which decreases the concentration of receptor molecules. The receptor gene may have a specific responsive element on its promoter whose action results in an inhibition of transcription of receptor mRNA or the receptor may stimulate transcription of a gene that codes for a protein that degrades the mRNA of the receptor. Sequences are now being recognized on receptor gene promoters that may bind activated steroid–receptor complexes and result in inhibition of transcription (Table 21.4). Downregulation of receptors by their own ligands plays an important physiological role because it prevents overstimulation of target cells when circulating hormone levels are elevated.
Although downregulation of steroid receptor levels by their cognate hormones appears to be the most frequently detected form of autoregulation, it is not common to all target cells. In fact, glucocorticoid­mediated upregulation has been reported in a number of responsive cells. Since all of these cells are growth inhibited by these hormones, it was initially suggested that hormone­mediated upregulation may be required for subsequent growth inhibition. However, the fact that glucocorticoid­
mediated upregulation also occurs in human lymphoid cells, which express glucocorticoid receptors but are not growth inhibited by these steroids, demonstrates that this positive autoregulation is neither the result nor cause of hormone­mediated growth arrest.
21.9— Specific Example of Steroid Hormone Action at Cell Level:
Programmed Death
Programmed cell death or apoptosis is a suicide process by which cells die according to a program that may be beneficial for the organism. It can result from the rise or fall in the level of a specific hormone(s). Uterine endometrial cells at the beginning of menstruation are an example where programmed cell death is initiated by the fall in levels of progesterone and estradiol in the blood (see Clin. Corr. 21.3). Another case is apoptosis of thymus cells during development when the adrenal cortex becomes functional and begins to synthesize and secrete relatively large amounts of cortisol. A newborn has a large thymus but when cortisol is synthesized and released the thymus cortical cells begin to die until a resistant core of cells is reached and the gland achieves its adult size. Thus programmed cell death is a mechanism used in development for the maturation of certain organs as well as in cyclic systems where cells