Mice with inactivation of aryl hydrocarbon receptor-interacting protein (Aip) display complete penetrance of pituitary adenomas with aberrant ARNT expression.
Title | Mice with inactivation of aryl hydrocarbon receptor-interacting protein (Aip) display complete penetrance of pituitary adenomas with aberrant ARNT expression. |
Publication Type | Journal Article |
Year of Publication | 2010 |
Authors | Raitila, A., Lehtonen H. J., Arola J., Heliövaara E., Ahlsten M., Georgitsi M., Jalanko A., Paetau A., Aaltonen L. A., & Karhu A. |
Journal | Am J Pathol |
Volume | 177 |
Issue | 4 |
Pagination | 1969-76 |
Date Published | 2010 Oct |
ISSN | 1525-2191 |
Keywords | Animals, Aryl Hydrocarbon Receptor Nuclear Translocator, Blotting, Western, Cell Proliferation, Female, Growth Hormone-Secreting Pituitary Adenoma, Humans, Immunoenzyme Techniques, Intracellular Signaling Peptides and Proteins, Loss of Heterozygosity, Male, Mice, Mice, Inbred C57BL, Reverse Transcriptase Polymerase Chain Reaction, RNA, Messenger |
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. |
DOI | 10.2353/ajpath.2010.100138 |
Alternate Journal | Am. J. Pathol. |
PubMed ID | 20709796 |
PubMed Central ID | PMC2947291 |