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

Authors
 Mary P. Gillam  ;  Cheol Ryong Ku  ;  Yang Jong Lee  ;  Jean Kim  ;  Se Hoon Kim  ;  Sue Ji Lee  ;  Byungjin Hwang  ;  JaeHyung Koo  ;  Rhonda D. Kineman  ;  Hiroaki Kiyokawa  ;  Eun Jig Lee 
Citation
 Journal of the Endocrine Society, Vol.1(2) : 78-95, 2017 
Journal Title
 Journal of the Endocrine Society 
Issue Date
2017
Keywords
aryl hydrocarbon receptor–interacting protein ; knockout mice ; pituitary adenoma predisposition ; pituitary hyperplasia ; pituitary tumor
Abstract
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.
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DOI
10.1210/js.2016-1004
Appears in Collections:
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실)
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실)
Yonsei Authors
구철룡(Ku, Cheol Ryong) ORCID logo https://orcid.org/0000-0001-8693-9630
김세훈(Kim, Se Hoon) ORCID logo https://orcid.org/0000-0001-7516-7372
이은직(Lee, Eun Jig) ORCID logo https://orcid.org/0000-0002-9876-8370
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URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/163348
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