Constitutive Somatostatin Receptor Subtype 2 Activity Attenuates GH Synthesis
| Autor: | Vera Chesnokova, Cuiqi Zhou, Anat Ben-Shlomo, Song-Guang Ren, Ramtin Khalafi, Oxana Pichurin, Ning-Ai Liu, Shlomo Melmed |
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| Rok vydání: | 2013 |
| Předmět: |
Male
Chromatin Immunoprecipitation medicine.medical_specialty Growth Hormone-Somatostatin-GRH Somatotropic cell medicine.drug_class Biology Mice Endocrinology Cell Line Tumor Internal medicine medicine Animals Humans Somatostatin receptor 2 Receptors Somatostatin Receptor Cell Proliferation Microscopy Confocal Somatostatin receptor Histone deacetylase inhibitor Immunohistochemistry Molecular biology Prolactin Rats Somatostatin Cell culture Growth Hormone Corticotropic cell Protein Binding |
| Zdroj: | Endocrinology. 154:2399-2409 |
| ISSN: | 1945-7170 0013-7227 |
| DOI: | 10.1210/en.2013-1132 |
| Popis: | Somatostatin signals predominantly through somatostatin receptor (SSTR) subtype 2 to attenuate GH release. However, the independent role of the receptor in regulating GH synthesis is unclear. Because we had previously demonstrated constitutive SSTR2 activity in mouse corticotrophs, we now analyzed GH regulation in rat pituitary somatotroph (GC) tumor cells, which express SSTR2 exclusively and are devoid of endogenous somatostatin ligand. We demonstrate that moderately stable SSTR2 overexpression (GpSSTR2WT cells) was associated with decreased GH promoter activity, GH mRNA, and hormone levels compared with those of control transfectants (GpCon cells). In contrast, levels of GH mRNA and peptide and GH promoter activity were unchanged in GpSSTR2DRY stable transfectants moderately expressing DRY motif mutated SSTR2 (R140A). GpSSTR2DRY did not exhibit an enhanced octreotide response as did GpSSTR2WT cells; however, both SSTR2WT-enhanced yellow fluorescent protein (eYFP) and SSTR2DRY-eYFP internalized on octreotide treatment. Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, increased GH synthesis in wild-type GC cells and primary pituitary cultures. GpSSTR2WT cells induced GH synthesis more strongly on SAHA treatment, evident by both higher GH peptide and mRNA levels compared with the moderate but similar GH increase observed in GpCon and GpSSTR2DRY cells. In vivo SAHA also increased GH release from GpSSTR2WT but not from control xenografts. Endogenous rat GH promoter chromatin immunoprecipitation showed decreased baseline acetylation of the GH promoter with exacerbated acetylation after SAHA treatment in GpSSTR2WT compared with that of either GpSSTR2DRY or control cells, the latter 2 transfectants exhibiting similar GH promoter acetylation levels. In conclusion, modestly increased SSTR2 expression constitutively decreases GH synthesis, an effect partially mediated by GH promoter histone deacetylation. |
| Databáze: | OpenAIRE |
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