Crabtree Judy S, 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
National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Mol Cell Biol. 2003 Sep;23(17):6075-85. doi: 10.1128/MCB.23.17.6075-6085.2003.
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.
1型多发性内分泌腺瘤病（MEN1）患者会发生多发性内分泌肿瘤，主要累及甲状旁腺、垂体和内分泌胰腺，这是由于MEN1基因失活所致。构建了一种条件性小鼠模型，以评估小鼠同源基因Men1在胰腺β细胞中的缺失情况。这些小鼠的Men1基因包含位于loxP位点两侧的外显子3至8，因此，当这些小鼠与从大鼠胰岛素启动子（RIP-cre）表达cre的转基因小鼠杂交时，β细胞中的外显子3至8会被删除。到60周龄时，>80%的纯合floxed Men1基因并表达RIP-cre的小鼠会发生多发性胰岛腺瘤。腺瘤的形成导致血清胰岛素水平升高和血糖水平降低。即使Men1的两个拷贝早期缺失，肿瘤出现仍有延迟，这意味着β细胞腺瘤形成还需要其他体细胞事件。对这些小鼠β细胞肿瘤DNA进行比较基因组杂交，发现11号染色体存在重复，这可能揭示了与肿瘤发生相关的感兴趣区域。
