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PMID: 12917331 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Of mice and MEN1: Insulinomas in a conditional mouse knockout.

Molecular and cellular biology ·Vol. 23 ·No. 17 ·2003-09-00 ·Pages 6075-85

Crabtree JS, Scacheri PC, Ward JM, McNally SR, Swain GP, Montagna C, Hager JH, Hanahan D, Edlund H, Magnuson MA, Garrett-Beal L, Burns AL, Ried T, Chandrasekharappa SC, Marx SJ, Spiegel AM, Collins FS

Abstract

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.

MeSH Terms
Adenoma/genetics,metabolism,pathology Animals Blood Glucose/metabolism Cell Division/genetics Cells, Cultured Disease-Free Survival Genetic Engineering/methods Heterozygote Homozygote Hyperplasia/genetics In Situ Hybridization/methods Insulin/genetics,metabolism Insulinoma/genetics,metabolism,pathology Integrases/genetics Islets of Langerhans/pathology,physiology Mice Mice, Knockout Mice, Transgenic Neoplasm Proteins/genetics,metabolism Pancreatic Neoplasms/genetics,metabolism,pathology Pituitary Gland/pathology Promoter Regions, Genetic Proto-Oncogene Proteins Sequence Deletion Viral Proteins/genetics
Chemicals
Blood Glucose Insulin MEN1 protein, human Neoplasm Proteins Proto-Oncogene Proteins Viral Proteins Cre recombinase Integrases
Authors & Affiliations
17 authors, click to expand affiliations / ORCID
Crabtree Judy S
National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Scacheri Peter C
Ward Jerrold M
McNally Sara R
Swain Gary P
Montagna Cristina
Hager Jeffrey H
Hanahan Douglas
Edlund Helena
Magnuson Mark A
Garrett-Beal Lisa
Burns A Lee
Ried Thomas
Chandrasekharappa Settara C
Marx Stephen J
Spiegel Allen M
Collins Francis S
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.23.17.6075-6085.2003
Published
2003-09-00
Pages
6075-85
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC180910
Subset
IM
Grants
NIDDK NIH HHS · P30 DK050306 · United States
NIDDK NIH HHS · P30 DK50306 · United States
External Links
PubMed source DOI: 10.1128/MCB.23.17.6075-6085.2003 PMC Full Text View journal details
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