ERC
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Endocrine-Related Cancer 16 (4) 1313 -1327     DOI: 10.1677/ERC-09-0082
Copyright © 2009 by the Society for Endocrinology
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
ERC-09-0082v1
ERC-09-0082v2
16/4/1313    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Google Scholar
Right arrow Articles by Harding, B.
Right arrow Articles by Thakker, R. V
PubMed
Right arrow PubMed Citation
Right arrow Articles by Harding, B.
Right arrow Articles by Thakker, R. V

Multiple endocrine neoplasia type 1 knockout mice develop parathyroid, pancreatic, pituitary and adrenal tumours with hypercalcaemia, hypophosphataemia and hypercorticosteronaemia

 Brian Harding*, Manuel C Lemos*, Anita A C Reed, Gerard V Walls, Jeshmi Jeyabalan, Michael R Bowl, Hilda Tateossian1, Nicky Sullivan2, Tertius Hough1, William D Fraser3, Olaf Ansorge2, Michael T Cheeseman1 and Rajesh V Thakker

Academic Endocrine Unit, Nuffield Department of Clinical Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Churchill Hospital, University of Oxford, Headington, Oxford OX3 7LJ, UK
1 Mammalian Genetics Unit and Mary Lyon Centre, Medical Research Council, Harwell, Oxfordshire OX11 0RD, UK
2 Department of Neuropathology, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK
3 Unit of Clinical Biochemistry, School of Clinical Sciences, University of Liverpool, Liverpool L69 3GA, UK

(Correspondence should be addressed to R V Thakker; Email: rajesh.thakker{at}ndm.ox.ac.uk)

* (B Harding and M C Lemos contributed equally to this work)

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized in man by parathyroid, pancreatic, pituitary and adrenal tumours. The MEN1 gene encodes a 610-amino acid protein (menin) which is a tumour suppressor. To investigate the in vivo role of menin, we developed a mouse model, by deleting Men1 exons 1 and 2 and investigated this for MEN1-associated tumours and serum abnormalities. Men1+/– mice were viable and fertile, and 220 Men1+/– and 94 Men1+/+ mice were studied between the ages of 3 and 21 months. Survival in Men1+/– mice was significantly lower than in Men1+/+ mice (<68% vs >85%, P<0.01). Men1+/– mice developed, by 9 months of age, parathyroid hyperplasia, pancreatic tumours which were mostly insulinomas, by 12 months of age, pituitary tumours which were mostly prolactinomas, and by 15 months parathyroid adenomas and adrenal cortical tumours. Loss of heterozygosity and menin expression was demonstrated in the tumours, consistent with a tumour suppressor role for the Men1 gene. Men1+/– mice with parathyroid neoplasms were hypercalcaemic and hypophosphataemic, with inappropriately normal serum parathyroid hormone concentrations. Pancreatic and pituitary tumours expressed chromogranin A (CgA), somatostatin receptor type 2 and vascular endothelial growth factor-A. Serum CgA concentrations in Men1+/– mice were not elevated. Adrenocortical tumours, which immunostained for 3-β-hydroxysteroid dehydrogenase, developed in seven Men1+/– mice, but resulted in hypercorticosteronaemia in one out of the four mice that were investigated. Thus, these Men1+/– mice are representative of MEN1 in man, and will help in investigating molecular mechanisms and treatments for endocrine tumours.






HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Copyright © 2009 by the Society for Endocrinology.