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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 Gene

Endocrine Unit (A.P., B.C., P.L., F.C., L.B., M.S.) and Medical Genetics Unit (S.B.-P.), Department of Clinical Physiopathology, University of Florence, 50139 Florence, Italy; and Institute of Endocrine Sciences, Ospedale Maggiore, University of Milan (S.C., E.B., A.S.), 20122 Milan, Italy

Address all correspondence and requests for reprints to: Alessandro Peri, M.D., Ph.D., Endocrine Unit, Department of Clinical Physiopathology, University of Florence, Viale Pieraccini, 6, 50139 Florence, Italy. E-mail: a.peri{at}dfc.unifi.it

In about 30–40% of GH-secreting adenomas, gain-of-function mutations of the Gs gene, which convert this gene into an oncogene termed gsp, occur. Gs mutations have been related to pituitary tumorigenesis. We focused on 2 nuclear transcription factors that are final targets of the cAMP-dependent pathway and are positively regulated by cAMP signaling, i.e. the cAMP-responsive element binding protein (CREB) and the inducible cAMP early repressor (ICER), that derives from alternative splicing of cAMP-responsive element modulator gene. We examined 21 GH-secreting adenomas, 8 with (gsp⁺) and 13 without (gsp^-) a mutated Gs. Analysis of CREB and ICER I/II messenger RNA revealed that the levels of both transcripts were higher in gsp⁺ than in gsp^- tumors (CREB/glyceraldehyde-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 between the levels of CREB and ICER transcripts was observed, suggesting the possible presence of alterations in the mechanisms by which cAMP signaling directs the expression of CREB and/or ICER genes. Our results indicate a complex pattern of expression of nuclear transcription factors that mediate cAMP action in both gsp⁺ and gsp^- tumors, suggesting that, beside Gs gene mutations, different and partially unknown molecular events may contribute to the pathogenesis of these tumors.

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