Study on the gene abnormalities that cause glucocorticoid-resistant POMC gene expression in corticotroph adenoma cells Cushing's disease

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To clarity the mechanism of hypersecretion of ACTH and the resistance of ACTH secretion to glucocorticoid, (1) gene expression of c-fos, (2) gene expression of CRF-R1, (3) response of ACTH to DDAVP and characterization of Vi b mRNA were studied in ACTH-producing pituitary adenoma cells.(1) c-f os Gene expression of c-fos in corticotroph adenoma cells was greater than that in non-adenoma cells. There were 2 point mutations (somatic mutation) at 5'-UTR in c-fos gene. Fos seems to bind to OR and inhibit OR-induced suppression of POMG gene expression. In addition, Fos may stimulate POMO gene expression.(2) CRF-R1 mRNA levels were down-regulated by CRF in corticotrophs, but were up-regulated by CRF in corticotroph adenoma cells. These CRF-induced down- and up-regulation of CRF-R1 mRNA levels were mediated by cAMP.VP and glucocorticoid down-regulated CRF-RI mRNA levels in both types of ACTH cells.(3) DDAVP, V2-agonist, stimulated ACTH secretion from corticotroph adenoma cells, but did not stimulate it in normal ACTH cells. Vib mRNA levels in corticotroph adenoma cells increased after stimulation of VP and CRF.The size of Vib mRNA in adenoma cells was similar to that of authentic V1 b mRNA.(4) Saikosaponin and serotonin stimulated GRF gene expression in the paraventricular nucleus of the hypothalamus in rats.