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Molecular and Cellular Biology, September 2003, p. 6075-6085, Vol. 23, No. 17
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.17.6075-6085.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Of Mice and MEN1: Insulinomas in a Conditional Mouse Knockout

Judy S. Crabtree,1 Peter C. Scacheri,1 Jerrold M. Ward,2 Sara R. McNally,3 Gary P. Swain,3 Cristina Montagna,4 Jeffrey H. Hager,5 Douglas Hanahan,5 Helena Edlund,6 Mark A. Magnuson,7 Lisa Garrett-Beal,1 A. Lee Burns,8 Thomas Ried,4 Settara C. Chandrasekharappa,1 Stephen J. Marx,8 Allen M. Spiegel,8 and Francis S. Collins1*

National Human Genome Research Institute,1 National Cancer Institute,4 National Institute of Diabetes and Digestive and Kidney Diseases,8 National Institutes of Health, Bethesda, Maryland 20892; National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702,2 Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104,3 Department of Biochemistry, University of California San Francisco, San Francisco, California 94143,5 Department of Microbiology, University of Umea, Umea S 901 87, Sweden,6 Vanderbilt University Medical Center, Nashville, Tennessee 372327

Received 7 January 2003/ Returned for modification 3 March 2003/ Accepted 21 May 2003

Patients with multiple endocrine neoplasia type 1 (MEN1) develop multiple endocrine tumors, primarily affecting the parathyroid, pituitary, and endocrine pancreas, due to the inactivation of the MEN1 gene. A conditional mouse model was developed to evaluate the loss of the mouse homolog, Men1, in the pancreatic beta cell. Men1 in these mice contains exons 3 to 8 flanked by loxP sites, such that, when the mice are crossed to transgenic mice expressing cre from the rat insulin promoter (RIP-cre), exons 3 to 8 are deleted in beta cells. By 60 weeks of age, >80% of mice homozygous for the floxed Men1 gene and expressing RIP-cre develop multiple pancreatic islet adenomas. The formation of adenomas results in elevated serum insulin levels and decreased blood glucose levels. The delay in tumor appearance, even with early loss of both copies of Men1, implies that additional somatic events are required for adenoma formation in beta cells. Comparative genomic hybridization of beta cell tumor DNA from these mice reveals duplication of chromosome 11, potentially revealing regions of interest with respect to tumorigenesis.

* Corresponding author. Mailing address: National Human Genome Research Institute, National Institutes of Health, Building 31, Rm. 4B09, Bethesda, MD 20892-2152. Phone: (301) 496-0844. Fax: (301) 402-0837. E-mail: fc23a{at}nih.gov.

Molecular and Cellular Biology, September 2003, p. 6075-6085, Vol. 23, No. 17
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.17.6075-6085.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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