Of mice and MEN1: Insulinomas in a conditional mouse knockout.
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.
Crabtree
Judy S
JS
National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Scacheri
Peter C
PC
Ward
Jerrold M
JM
McNally
Sara R
SR
Swain
Gary P
GP
Montagna
Cristina
C
Hager
Jeffrey H
JH
Hanahan
Douglas
D
Edlund
Helena
H
Magnuson
Mark A
MA
Garrett-Beal
Lisa
L
Burns
A Lee
AL
Ried
Thomas
T
Chandrasekharappa
Settara C
SC
Marx
Stephen J
SJ
Spiegel
Allen M
AM
Collins
Francis S
FS
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
D001786:Blood Glucose; D007328:Insulin; C105373:MEN1 protein, human; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D014764:Viral Proteins; C045073:Cre recombinase; D019426:Integrases