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Somatotroph-Specific Aip-Deficient Mice Display Pretumorigenic Alterations in Cell-Cycle Signaling

Somatotroph-Specific Aip-Deficient Mice Display Pretumorigenic Alterations in Cell-Cycle Signaling
Mary GillamCheol Ryong KuLee, Yang JongKim, JeanKim, Se HoonLee, Sue JiHwang, ByungjinKoo, Jae HyungKieman, RhondaKiyokawa, HiroakiLee, Eun Jig
DGIST Authors
Koo, Jae Hyung
Issue Date
Journal of the Endocrine Society, 1(2), 78-95
aryl hydrocarbon receptor–interacting proteinknockout micepituitary adenoma predispositionpituitary hyperplasiapituitary tumor
Patients with familial isolated pituitary adenoma are predisposed to pituitary adenomas, which in a subset of cases is due to germline inactivating mutations of the aryl hydrocarbon receptor–interacting protein (AIP) gene. Using Cre/lox and Flp/Frt technology, a conditional mouse model was generated to examine the loss of the mouse homolog, Aip, in pituitary somatotrophs. By 40 weeks of age, >80% of somatotroph specific Aip knockout mice develop growth hormone (GH) secreting adenomas. The formation of adenomas results in physiologic effects recapitulating the human syndrome of acromegaly, including increased body size, elevated serum GH and insulin-like growth factor 1 levels, and glucose intolerance. The pretumorigenic Aip-deficient somatotrophs secrete excess GH and exhibit pathologic hyperplasia associated with cytosolic compartmentalization of the cyclin-dependent kinase (CDK) inhibitor p27kip1 and perinuclear accentuation of CDK-4. Following tumor formation, the Aip-deficient somatotrophs display reduced expression of somatostatin receptor subtype 5 with impaired response to octreotide. The delayed tumor emergence, even with loss of both copies of Aip, implies that additional somatic events are required for adenoma formation. These findings suggest that pituitary hyperplasia precedes adenomatous transformation in somatotroph-specific Aip-deficient mice and reveal potential mechanisms involved in the pretumorigenic state that ultimately contribute to transformation.
Endocrine Society | Oxford University Press
Related Researcher
  • Author Koo, JaeHyung Molecular & Cellular Smell Biology Lab
  • Research Interests Neurotranslation and chemosensation; 화학감각신경(후각, 미각) 및 이소성후각수용체 연구와 응용
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Department of Brain and Cognitive SciencesMolecular & Cellular Smell Biology Lab1. Journal Articles

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