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Use of the Metallothionein Promoter-Human Growth Hormone-Releasing Hormone (GHRH) Mouse to Identify Regulatory Pathways that Suppress Pituitary Somatotrope Hyperplasia and Adenoma Formation due to GHRH-Receptor Hyperactivation

Research and Development Division (R.M.L., S.K., R.D.K.), Jesse Brown Veterans Affairs Medical Center and Department of Medicine (R.M.L., B.S.S., X.P., S.K., J.C.-C., L.A.F., R.D.K.), Section of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago, Chicago, Illinois 60612; and Department of Cell Biology, Physiology, and Immunology (R.M.L., J.C.-C.), University of Cordoba, 14004 Córdoba, Spain

Address all correspondence and requests for reprints to: Rhonda D. Kineman, Ph.D., Research Health Scientist, Jesse Brown Veterans Affairs Medical Center, Research and Development Division, M.P. 151, West Side, Suite 6215, 820 South Damen Avenue, Chicago, Illinois 60612. E-mail: kineman{at}uic.edu.

Hyperactivation of the GHRH receptor or downstream signaling components is associated with hyperplasia of the pituitary somatotrope population, in which adenomas form relatively late in life, with less than 100% penetrance. Hyperplastic and adenomatous pituitaries of metallothionein promoter-human GHRH transgenic (Tg) mice (4 and > 10 months, respectively) were used to identify mechanisms that may prevent or delay adenoma formation in the presence of excess GHRH. In hyperplastic pituitaries, expression of the late G₁/G₂ marker Ki67 increased, whereas the proportion of 5-bromo-2'-deoxyuridine-labeled cells (S phase marker) did not differ from age-matched controls. These results indicate cell cycle progression is blocked, with further evidence suggesting that enhanced p27 activity may contribute to this process. For adenomas, formation was associated with loss of p27 activity (nuclear localization and mRNA). Increased endogenous somatostatin (SST) tone may also slow the conversion from hyperplastic to adenomatous state because mRNA levels for SST receptors, sst2 and sst5, were elevated in hyperplastic pituitaries, whereas adenomas were associated with a decline in sst1 and sst5 mRNA. Also, SST-knockout Tg pituitaries were larger and adenomas formed earlier compared with those of SST-intact Tg mice. Unexpectedly, these changes were independent of changes in proliferation rate within the hyperplastic tissue, suggesting that endogenous SST controls GHRH-induced adenoma formation primarily via modulation of apoptotic and/or cellular senescence pathways, consistent with the predicted function of some of the most differentially expressed genes (Casp1, MAP2K1, TNFR2) identified by membrane arrays and confirmed by quantitative real-time RT-PCR.