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Molecular and Cellular Biology, April 2004, p. 3125-3131, Vol. 24, No. 8
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.8.3125-3131.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Conditional Inactivation of the Men1 Gene Leads to Pancreatic and Pituitary Tumorigenesis but Does Not Affect Normal Development of These Tissues

Christine A. Biondi,1,{dagger} Michael G. Gartside,1 Paul Waring,2,3 Kelly A. Loffler,1 Mitchell S. Stark,1 Mark A. Magnuson,4 Graham F. Kay,1 and Nicholas K. Hayward1*

Queensland Institute of Medical Research, Herston, Queensland,1 Department of Pathology, Peter MacCallum Cancer Institute, East Melbourne,2 Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia,3 Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee4

Received 23 October 2003/ Accepted 8 January 2004

Mutations of the MEN1 gene, encoding the tumor suppressor menin, predispose individuals to the cancer syndrome multiple endocrine neoplasia type 1, characterized by the development of tumors of the endocrine pancreas and anterior pituitary and parathyroid glands. We have targeted the murine Men1 gene by using Cre recombinase-loxP technology to develop both total and tissue-specific knockouts of the gene. Conditional homozygous inactivation of the Men1 gene in the pituitary gland and endocrine pancreas bypasses the embryonic lethality associated with a constitutional Men1-/- genotype and leads to ß-cell hyperplasia in less than 4 months and insulinomas and prolactinomas starting at 9 months. The pituitary gland and pancreas develop normally in the conditional absence of menin, but loss of this transcriptional cofactor is sufficient to cause ß-cell hyperplasia in some islets; however, such loss is not sufficient to initiate pituitary gland tumorigenesis, suggesting that additional genetic events are necessary for the latter.

* Corresponding author. Mailing address: Queensland Institute of Medical Research, 300 Herston Rd., Herston, Queensland 4029, Australia. Phone: 61-7-3362 0308. Fax: 61-7-3845 3508. E-mail: nickH{at}qimr.edu.au.

{dagger} Present address: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.

Molecular and Cellular Biology, April 2004, p. 3125-3131, Vol. 24, No. 8
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.8.3125-3131.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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