Biondi Christine A, Gartside Michael G, Waring Paul, Loffler Kelly A, Stark Mitchell S, Magnuson Mark A, Kay Graham F, Hayward Nicholas K
Queensland Institute of Medical Research, Herston, Queensland, Australia.
Mol Cell Biol. 2004 Apr;24(8):3125-31. doi: 10.1128/MCB.24.8.3125-3131.2004.
Mutations of the MEN1 gene, encoding the tumor suppressor menin, predispose individuals to the cancer syndrome multiple endocrine neoplasia type 1, characterized by the development of tumors of the endocrine pancreas and anterior pituitary and parathyroid glands. We have targeted the murine Men1 gene by using Cre recombinase-loxP technology to develop both total and tissue-specific knockouts of the gene. Conditional homozygous inactivation of the Men1 gene in the pituitary gland and endocrine pancreas bypasses the embryonic lethality associated with a constitutional Men1(-/-) genotype and leads to beta-cell hyperplasia in less than 4 months and insulinomas and prolactinomas starting at 9 months. The pituitary gland and pancreas develop normally in the conditional absence of menin, but loss of this transcriptional cofactor is sufficient to cause beta-cell hyperplasia in some islets; however, such loss is not sufficient to initiate pituitary gland tumorigenesis, suggesting that additional genetic events are necessary for the latter.
编码肿瘤抑制因子menin的MEN1基因突变，使个体易患多发性内分泌肿瘤1型癌症综合征，其特征是内分泌胰腺、垂体前叶和甲状旁腺发生肿瘤。我们利用Cre重组酶-loxP技术靶向小鼠Men1基因，以构建该基因的完全敲除和组织特异性敲除模型。垂体和内分泌胰腺中Men1基因的条件性纯合失活绕过了与组成型Men1(-/-)基因型相关的胚胎致死性，并在不到4个月时导致β细胞增生，9个月时开始出现胰岛素瘤和催乳素瘤。在条件性缺失menin的情况下，垂体和胰腺正常发育，但这种转录辅因子的缺失足以在一些胰岛中引起β细胞增生；然而，这种缺失不足以引发垂体肿瘤发生，这表明垂体肿瘤发生还需要其他遗传事件。
