Adrenomedullin (ADM) is a
polypeptide originally discovered in a human
pheochromocytoma and is also present in normal adrenal medulla. It has been proposed that ADM could be involved in the regulation of adrenal steroidogenesis via paracrine mechanisms. Our aim was to find out if ADM gene is expressed in adrenocortical
tumors and how ADM gene expression is regulated in adrenal cells. ADM
mRNA was detectable by Northern blotting in most normal and hyperplastic adrenals,
adenomas and
carcinomas. The average concentration of ADM
mRNA in the hormonally active
adrenocortical adenomas was about 80% and 7% of that in normal adrenal glands and separated adrenal medulla respectively. In
adrenocortical carcinomas, the ADM
mRNA concentration was very variable, but on average it was about six times greater than that in normal adrenal glands. In
pheochromocytomas, ADM
mRNA expression was about ten times greater than that in normal adrenals and three times greater than in separated adrenal medulla. In primary cultures of normal adrenal cells, a
protein kinase C inhibitor,
staurosporine, reduced ADM
mRNA accumulation in a dose- and time-dependent fashion (P < 0.01), whereas it simultaneously increased the expression of human
cholesterol side-chain cleavage enzyme (P450 scc) gene (a key gene in steroidogenesis). In cultured Cushing's
adenoma cells,
adrenocorticotropin, dibutyryl cAMP ((Bu)2cAMP) and
staurosporine inhibited the accumulation of ADM
mRNA by 40, 50 and 70% respectively (P < 0.05), whereas the
protein kinase C activator,
12-O-tetradecanoyl phorbol 13-acetate (TPA), increased it by 50% (P < 0.05). In primary cultures of
pheochromocytoma cells, treatment with (Bu)2cAMP for 1 and 3 days increased ADM
mRNA accumulation two- to threefold (P < 0.05). Our results show that ADM
mRNA is present not only in adrenal medulla and
pheochromocytomas, but also in adrenocortical
neoplasms. Both
protein kinase A- and C-dependent mechanisms regulate ADM
mRNA expression in adrenocortical and
pheochromocytoma cells supporting the suggested role for ADM as an autocrine or paracrine (or both) regulator of adrenal function.