EXPRESSION OF AN ACTIVATED NOTCH-RELATED INT-3 TRANSGENE INTERFERES WITH CELL-DIFFERENTIATION AND INDUCES NEOPLASTIC TRANSFORMATION IN MAMMARY AND SALIVARY-GLANDS
EXPRESSION OF AN ACTIVATED NOTCH-RELATED INT-3 TRANSGENE INTERFERES WITH CELL-DIFFERENTIATION AND INDUCES NEOPLASTIC TRANSFORMATION IN MAMMARY AND SALIVARY-GLANDS
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DOI：
10.1101/gad.6.3.345
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发表时间：
1992-03-01
影响因子：
10.5
通讯作者：
CALLAHAN, R
中科院分区：
文献类型：
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作者：
JHAPPAN, C;GALLAHAN, D;CALLAHAN, R
由于小鼠乳腺肿瘤病毒 (MMTV) 插入诱变，int-3 基因座的表达在小鼠乳腺肿瘤中被激活。 MMTV 原病毒整合到 int-3 基因座中，促进侧翼细胞 int-3 序列的转录和翻译，该序列与果蝇神经源性 Notch 基因的细胞内结构域以及酵母细胞周期调节基因 cdc10 和 SWI6 具有显着的同源性。为了确定激活的 int-3 表达的体内后果，产生了含有由 MMTV LTR 和侧翼细胞 int-3 序列组成的基因组肿瘤 DNA 片段的转基因小鼠。所有六只 int-3 创始转基因小鼠和一个已建立品系的后代在表达转基因的组织中表现出类似的显着表型异常。大多数 2 至 7 个月大的转基因小鼠中出现局灶性且常常是多发性低分化乳腺癌和唾液腺癌。值得注意的是，所有雌性 int-3 小鼠的乳腺发育均受到抑制且泌乳不足。幼年和成年转基因小鼠的唾液腺、鼻粘膜和上颌窦腺体、眶外泪腺和哈德氏腺均含有增殖的未成熟小管细胞，且分化不完全。此外，所有雄性int-3转基因小鼠均不育，这显然是附睾严重增生的结果。这些发现在体内证明，激活的Notch相关int-3基因的表达会导致正常发育控制失调和腺上皮细胞过度增殖。
Expression of the int-3 locus is activated in mouse mammary tumors as a consequence of insertional mutagenesis by the mouse mammary tumor virus (MMTV). Integration of the MMTV provirus into the int-3 locus promotes the transcription and translation of flanking cellular int-3 sequences sharing significant homology with the intracellular domain of the neurogenic Notch gene of Drosophila, and with the yeast cell cycle regulatory genes cdc10 and SWI6. To determine the in vivo consequences of activated int-3 expression, transgenic mice were generated harboring a genomic tumor DNA fragment consisting of the MMTV LTR and the flanking cellular int-3 sequences. All six int-3 founder transgenic mice and the progeny of one established line exhibited similar dramatic phenotypic abnormalities in tissues in which the transgene was expressed. Focal and often multiple poorly differentiated mammary and salivary adenocarcinomas appeared in the majority of transgenic mice between 2 and 7 months of age. Significantly, mammary glands were arrested in development and were lactation deficient in all female int-3 mice. The salivary glands, glands of the nasal mucosa and maxillary sinus, the extraorbital lacrimal glands, and the Harderian glands of juvenile and adult transgenic mice all contained proliferating immature ductule cells and were incompletely differentiated. In addition, all male int-3 transgenic mice were sterile, apparently the result of severe hyperplasia of the epididymis. These findings demonstrate in vivo that expression of the activated Notch-related int-3 gene causes deregulation of normal developmental controls and hyperproliferation of glandular epithelia.