The regulation of the
ACTH-receptor gene is unique in that it is up-regulated by its own
ligand,
ACTH.
Ligand-induced up-regulation of
ACTH-receptor expression may be an important adaptive process directed towards optimizing adrenal responsiveness to
ACTH in the context of physiological stress and the maintenance of metabolic homeostasis in which the adrenals play a pivotal role. Whereas enhancement by
ligand-induced up-regulation permits a more efficient and rapid
glucocorticoid response, negative feedback regulation of
glucocorticoids in the hypothalamus and pituitary inhibits
ACTH secretion and allows a balanced adrenal response to stress. Since the cloning of the promoter region of the
ACTH receptor, considerable progress in the understanding of the regulatory processes has been made. The effects of
ACTH on
ACTH-receptor expression is dependent on cAMP, probably mediated through
AP-1. The profound effect of three SF-1-binding sites in the
ACTH-receptor promoter was demonstrated by deletion experiments. Conversely,
ACTH-receptor expression can be suppressed by adrenal-specific
transcription factors,like DAX-1. Despite an extensive search, no activating
ACTH-receptor mutations have been found in adrenal
tumors,excluding the
ACTH receptor as a relevant oncogene in adrenal
tumorigenesis. However, the
ACTH receptor may act as a differentiation factor as suggested by LOH in adrenal
carcinomas with an undifferentiated
tumor type. In benign adrenal
tumors, a strong correlation between
ACTH-receptor expression and expression of P450 steroidogenic
enzymes is evident. This close regulative relationship is lost in adrenal
carcinoma, probably as a result of
tumor dedifferentiation. Down-regulation of
ACTH-receptor expression in normal and neoplastic tissue can be achieved by adrenostatic compounds such as
aminoglutethimide and
metyrapone.