Pancreatic beta-cell-specific ablation of the multiple endocrine neoplasia type 1 (MEN1) gene causes full penetrance of insulinoma development in mice.
The function of the predisposition gene to multiple endocrine neoplasia type 1 (MEN1) syndrome remains largely unknown. Previous studies demonstrated that null mutation of the Men1 gene caused mid-gestation lethality in mice, whereas heterozygous Men1 knockout mice developed multiple endocrine tumors late in life. To seek direct evidence on the causal role of menin in suppressing tumor development, we generated mice in which the Men1 gene was disrupted specifically in pancreatic beta cells. These mice began to develop hyperplastic islets at as early as 2 months of age and insulinomas at 6 months of age. The islet lesions exhibited features of multistage tumor progression, including beta-cell dedifferentiation, angiogenesis, and altered expression of both E-cadherin and beta-catenin. Additionally, disturbance of blood insulin and glucose levels correlated with tumor development, mimicking human MEN1 symptoms. Our data indicate that this strain of mice provides a powerful tool for the study of the mechanisms of tumorigenesis related to MEN1 disease.
Bertolino
Philippe
P
Genetic and Cancer Laboratory, CNRS, UMR5641, Faculty of Medicine University Lyon 1, 69373, Lyon, France.
Tong
Wei-Min
WM
Herrera
Pedro Luis
PL
Casse
Huguette
H
Zhang
Chang Xian
CX
Wang
Zhao-Qi
ZQ
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003598:Cytoskeletal Proteins / Q000032:analysis; D017353:Gene Deletion; D007328:Insulin / Q000097:blood; D007340:Insulinoma / Q000209:etiology*; D007515:Islets of Langerhans / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000209:etiology*; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators / Q000032:analysis; D051176:beta Catenin
D001786:Blood Glucose; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D007328:Insulin; C105373:MEN1 protein, human; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D051176:beta Catenin