Expression of cyclic adenosine 3 ',5 '-monophosphate (cAMP)-responsive element binding protein and inducible-cAMP early repressor genes in growth hormone-secreting pituitary adenomas with or without mutations of the Gs alphagene

In about 30-40% of GH-secreting adenomas, gain-of-function mutations of the Gs alpha gene, which convert this gene into an oncogene termed gsp, occur. Gs alpha mutations have been related to pituitary tumorigenesis. We focuse d on 2 nuclear transcription factors that are final targets of the cAMP-dep endent pathway and are positively regulated by cAMP signaling, i.e. the cAM P-responsive element binding protein (CREB) and the inducible cAMP early re pressor (ICER), that derives from alternative splicing of cAMP-responsive e lement modulator gene. We examined 21 GH-secreting adenomas, 8 with (gsp(+) ) and 13 without (gsp(-)) a mutated Gs alpha. Analysis of CREB and ICER III I messenger RNA revealed that the levels of both transcripts were higher in gsp(+) than in gsp- tumors (CREB/glyceraldlehyde-3-phosphate dehydrogenase (GAPDH) mean optical density +/- SE, 2.34 +/- 0.36 in gsp(+) vs. 0.99 +/- 0.22 in gsp(-), P = 0.003; ICER I/GAPDH, 0.53 +/- 0.15 in gsp(+) vs. 0.14 /- 0.07 in gsp(-), P = 0.01; ICER II/GAPDH, 1.5 +/- 0.21 in gsp(+) vs. 0.83 +/- 0.13 in gsp(-), P = 0.01), although a few cases in both groups did not display this pattern of expression. Moreover, no positive correlation betw een the levels of CREB and ICER transcripts was observed, suggesting the po ssible presence of alterations in the mechanisms by which cAMP signaling di rects the expression of CREB and/or ICER genes. Our results indicate a comp lex pattern of expression of nuclear transcription factors that mediate cAM P action in both gsp(+) and gsp(-) tumors, suggesting that, beside Gs alpha gene mutations, different and partially unknown molecular events may contr ibute to the pathogenesis of these tumors.