title: Of mice and MEN1: Insulinomas in a conditional mouse knockout.
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.
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Judy S
authors.initials: JS
authors.lastname: Crabtree
authors.forename: Peter C
authors.initials: PC
authors.lastname: Scacheri
authors.forename: Jerrold M
authors.initials: JM
authors.lastname: Ward
authors.forename: Sara R
authors.initials: SR
authors.lastname: McNally
authors.forename: Gary P
authors.initials: GP
authors.lastname: Swain
authors.forename: Cristina
authors.initials: C
authors.lastname: Montagna
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Hager
authors.forename: Douglas
authors.initials: D
authors.lastname: Hanahan
authors.forename: Helena
authors.initials: H
authors.lastname: Edlund
authors.forename: Mark A
authors.initials: MA
authors.lastname: Magnuson
authors.forename: Lisa
authors.initials: L
authors.lastname: Garrett-Beal
authors.forename: A Lee
authors.initials: AL
authors.lastname: Burns
authors.forename: Thomas
authors.initials: T
authors.lastname: Ried
authors.forename: Settara C
authors.initials: SC
authors.lastname: Chandrasekharappa
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Marx
authors.forename: Allen M
authors.initials: AM
authors.lastname: Spiegel
authors.forename: Francis S
authors.initials: FS
authors.lastname: Collins
mesh_terms: D000236:Adenoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002455:Cell Division / Q000235:genetics; D002478:Cells, Cultured; D018572:Disease-Free Survival; D005818:Genetic Engineering / Q000379:methods; D006579:Heterozygote; D006720:Homozygote; D006965:Hyperplasia / Q000235:genetics; D017403:In Situ Hybridization / Q000379:methods; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D007340:Insulinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019426:Integrases / Q000235:genetics; D007515:Islets of Langerhans / Q000473:pathology / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010902:Pituitary Gland / Q000473:pathology; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins; D017384:Sequence Deletion; D014764:Viral Proteins / Q000235:genetics
chemical_list: D001786:Blood Glucose; D007328:Insulin; C105373:MEN1 protein, human; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D014764:Viral Proteins; C045073:Cre recombinase; D019426:Integrases