ACTH and related peptides: molecular biology, biochemistry and regulation of secretion.

The precursor of ACTH and beta-LPH is a glycoprotein with a molecular weight of more than 30 000. Its gene consists of three exons with two intervening sequences and most of the protein coding sequence is in exon 3. The gene is expressed not only in the pituitary gland but also in extrapituitary tissues. The gene expression in the anterior pituitary gland is regulated by CRF and glucocorticoids, but it is regulated differently in other tissues. The processing of the ACTH/beta-LPH precursor yields several peptides, but final products vary in tissues due to differential processing. The processing is abnormal in ACTH-producing tumours, especially in ectopic ACTH-producing tumours. Some abnormalities may also occur at the transcriptional or post-transcriptional level as well. Peptides derived from the same precursor are secreted concomitantly from the pituitary gland. CRF is the major stimulating factor, but vasopressin and some other factors are also involved in stimulating ACTH release. On the other hand, glucocorticoids inhibit ACTH release by acting at the hypothalamic and pituitary levels. In the pituitary ACTH-producing adenomas of Cushing's disease, CRF, vasopressin as well as other non-physiological factors stimulate ACTH secretion. Such abnormal receptor mechanisms are also seen in ectopic ACTH-producing tumours.