RRC ID 47321
著者 Fukuda T, Tanaka T, Hamaguchi Y, Kawanami T, Nomiyama T, Yanase T.
タイトル Augmented Growth Hormone Secretion and Stat3 Phosphorylation in an Aryl Hydrocarbon Receptor Interacting Protein (AIP)-Disrupted Somatotroph Cell Line.
ジャーナル PLoS One
Abstract Aryl hydrocarbon receptor interacting protein (AIP) is thought to be a tumor suppressor gene, as indicated by a mutational analysis of pituitary somatotroph adenomas. However, the physiological significance of AIP inactivation in somatotroph cells remains unclear. Using CRISPR/Cas9, we identified a GH3 cell clone (termed GH3-FTY) in which Aip was genetically disrupted, and subsequently investigated its character with respect to growth hormone (Gh) synthesis and proliferation. Compared with GH3, GH3-FTY cells showed remarkably increased Gh production and a slight increase in cell proliferation. Gh-induced Stat3 phosphorylation is known to be a mechanism of Gh oversecretion in GH3. Interestingly, phosphorylated-Stat3 expression in GH3-FTY cells was increased more compared with GH3 cells, suggesting a stronger drive for this mechanism in GH3-FTY. The phenotypes of GH3-FTY concerning Gh overproduction, cell proliferation, and increased Stat3 phosphorylation were significantly reversed by the exogenous expression of Aip. GH3-FTY cells were less sensitive to somatostatin than GH3 cells in the suppression of cell proliferation, which might be associated with the reduced expression of somatostatin receptor type 2. GH3-FTY xenografts in BALB/c nude mice (GH3-FTY mice) formed more mitotic somatotroph tumors than GH3 xenografts (GH3 mice), as also evidenced by increased Ki67 scores. GH3-FTY mice were also much larger and had significantly higher plasma Gh levels than GH3 mice. Furthermore, GH3-FTY mice showed relative insulin resistance compared with GH3 mice. In conclusion, we established a somatotroph cell line, GH3-FTY, which possessed prominent Gh secretion and mitotic features associated with the disruption of Aip.
巻・号 11(10)
ページ e0164131
公開日 2016-1-1
DOI 10.1371/journal.pone.0164131
PII PONE-D-16-14238
PMID 27706259
PMC PMC5051713
MeSH Adenoma / pathology* Animals Cell Line Cell Proliferation Gene Silencing Growth Hormone / metabolism* Growth Hormone-Secreting Pituitary Adenoma / pathology* Intracellular Signaling Peptides and Proteins / genetics* Intracellular Signaling Peptides and Proteins / metabolism Mice Mice, Inbred BALB C Neoplasm Transplantation Phosphorylation Rats Rho Guanine Nucleotide Exchange Factors / metabolism* STAT3 Transcription Factor / metabolism* Somatotrophs / cytology* Somatotrophs / metabolism Somatotrophs / transplantation Up-Regulation
IF 2.74
引用数 4
WOS 分野 ENDOCRINOLOGY & METABOLISM
リソース情報
遺伝子材料 CSII-EF-Venus (RDB05552)