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Mice with inactivation of aryl hydrocarbon receptor-interacting protein (Aip) display complete penetrance of pituitary adenomas with aberrant ARNT expression.

Abstract
Mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene have been shown to predispose to pituitary adenoma predisposition, a condition characterized by growth hormone (GH)-secreting pituitary tumors. To study AIP-mediated tumorigenesis, we generated an Aip mouse model. Heterozygous mice developed normally but were prone to pituitary adenomas, in particular to those secreting GH. A complete loss of AIP was detected in these lesions, and full penetrance was reached at the age of 15 months. No excess of any other tumor type was found. Ki-67 analysis indicated that Aip-deficient tumors have higher proliferation rates compared with Aip-proficient tumors, suggesting a more aggressive disease. Similar to human AIP-deficient pituitary adenomas, immunohistochemical studies showed that expression of aryl hydrocarbon receptor nuclear translocator 1 or 2 (ARNT or ARNT2) protein was lost in the mouse tumors, suggesting that mechanisms of AIP-related tumorigenesis involve aberrant ARNT function. The Aip(+/-) mouse appears to be an excellent model for the respective human disease phenotype. This model constitutes a tool to further study AIP-associated pituitary tumorigenesis and may be potentially valuable in efforts to develop therapeutic strategies to treat pituitary adenomas.
AuthorsAnniina Raitila, Heli J Lehtonen, Johanna Arola, Elina Heliövaara, Manuel Ahlsten, Marianthi Georgitsi, Anu Jalanko, Anders Paetau, Lauri A Aaltonen, Auli Karhu
JournalThe American journal of pathology (Am J Pathol) Vol. 177 Issue 4 Pg. 1969-76 (Oct 2010) ISSN: 1525-2191 [Electronic] United States
PMID20709796 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Arnt protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • RNA, Messenger
  • aryl hydrocarbon receptor-interacting protein
  • Aryl Hydrocarbon Receptor Nuclear Translocator
Topics
  • Animals
  • Aryl Hydrocarbon Receptor Nuclear Translocator (genetics, metabolism)
  • Blotting, Western
  • Cell Proliferation
  • Female
  • Growth Hormone-Secreting Pituitary Adenoma (etiology, metabolism, pathology)
  • Humans
  • Immunoenzyme Techniques
  • Intracellular Signaling Peptides and Proteins (physiology)
  • Loss of Heterozygosity
  • Male
  • Mice
  • Mice, Inbred C57BL
  • RNA, Messenger (genetics)
  • Reverse Transcriptase Polymerase Chain Reaction

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