A primary function of the adrenal cortex is the production of glucocorticoids and mineralocorticoids, steroid hormones that play indispensable roles in maintenance of the internal milieu. The adrenal cortex, however, is capable of producing all known classes of biologically active steroids, including estrogens, androgens and progestens. It is unclear what biological effect these steroids may have on the adrenocortical cell. In addition, many steroids produced by the adrenal cortex are products of reactions that branch from general synthetic schemes and the biological import of these metabolic products is also not known. The research program of the SACB is concerned with the complex process of steroidogenesis in the mammalian adrenal cortex, a process that encompasses both steroid biosynthesis and steroid metabolism. Current research is focused on elucidating the functional role of three unique adrenocortical steroid-binding proteins, two of which are cytosolic while the third is a nuclear protein. The nuclear protein, which specifically binds progesterone with high affinity, binds to DNA and is regulated by ACTH. The possibility that the nuclear progesterone-binding protein represents a truncated C-terminal 50 kDa form of the progesterone receptor that contains the steroid- and DNA-binding domains is under investigation. The two cytosolic proteins require a co-factor that we have identified as 3', 5'-adenosine diphosphate for steroid binding activity. We have also determined that the cytosolic steroid-binding proteins belong to a poorly understood class of adrenocortical enzymes known as steroid sulfotransferases. One of the cytosolic proteins binds pregnenolone (PST), the product of the rate-limiting step in steroid synthesis. This protein has now been isolated, sequenced and is currently being cloned. The other cytosolic protein, which binds estradiol (EST), has been purified and the cDNA cloned and expressed; furthermore, the 5'-flanking region of the cognate gene for EST has been cloned revealing motifs related to steroid response elements. In addition to cis-acting elements, transacting factors have also been discovered. The mammalian adrenal cortex is composed of three concentric zones, each consisting of more or less uniform populations of cells that are differentially hormonally regulated. Immunocytochemical studies indicate that PST is present only in reticularis cells of the innermost zone, EST is present in reticularis and fasciculata cells (middle zone), while glomerulosa cells of the outermost zone contain neither protein. Thus, this becomes an interesting model in which to examine the differential expression of specific genes.
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