Enhanced expression of mRNA coding for the adrenaline-synthesizing enzyme phenylethanolamine-N-methyl transferase in adrenaline-secreting pheochromocytomas.
OBJECTIVE
In some pheochromocytomas, the tumors contain and secrete greater amounts of adrenaline than do normal adrenal medullas. It is not yet known how adrenaline synthesis is enhanced in the adrenaline-secreting pheochromocytomas.


METHODS
As a first step toward understanding the molecular mechanisms by which adrenaline synthesis is controlled in these tumors, we measured the level of mRNA coding for the adrenaline-synthesizing enzyme phenylethanolamine N-methyl transferase (PNMT) and the content of adrenaline in the pheochromocytomas (n = 9), including 3 cases of the adrenaline-secreting type (one of the patients had bilateral pheochromocytomas), and in normal adrenal medullas (n = 7). We then measured the concentration of cortisol, which is thought to regulate the PNMT activity. Finally, we examined the expression of the mRNA for Egr-1, which was recently reported to be a transcriptional factor regulating PNMT gene expression.


RESULTS
In the 4 tissue specimens from 3 adrenaline-secreting pheochromocytomas, the contents of adrenaline and the PNMT mRNA expression were considerably greater than those of the normal adrenal medullas. PNMT immunoreactivity was only detected in the adrenaline-secreting tumors. Three of the 4 specimens showed high concentrations of cortisol. To show the capacity for cortisol production locally in the pheochromocytoma tissues, we showed the expression of a glucocorticoid biosynthetic enzyme, 17alpha-hydroxylase, in the tumors by Western blotting. PNMT expression was found to be associated with 17alpha-hydroxylase expression in the tumors. The glucocorticoid receptor expression was also correlated with PNMT expression in the tumors and the expression of Egr-1 was also high in 3 of the 4 specimens.


CONCLUSIONS
These findings indicate that adrenaline production in adrenaline-secreting pheochromocytomas is primarily controlled by the level of PNMT gene expression, and that the gene expression may be enhanced by both cortisol and Egr-1.
Isobe
K
K
Department of Clinical Pathology, Institute of Clinical Medicine, University of Tsukuba, Japan.
Nakai
T
T
Yashiro
T
T
Nanmoku
T
T
Yukimasa
N
N
Ikezawa
T
T
Suzuki
E
E
Takekoshi
K
K
Nomura
F
F
D000310:Adrenal Gland Neoplasms / Q000378:metabolism*; D004837:Epinephrine / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D010625:Phenylethanolamine N-Methyltransferase / Q000235:genetics*; D010673:Pheochromocytoma / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis*
D012333:RNA, Messenger; D010625:Phenylethanolamine N-Methyltransferase; D004837:Epinephrine