Functional analysis of truncated Notch 1 gene products generated by insertions of mouse mammary tumor proviruses in development of mouse lymphomas.

Notch基因家族编码一种跨膜受体，在果蝇和脊椎动物的整个发育过程中控制细胞的命运决定。Notch蛋白的氨基末端编码胞外结构域，包含多达36个重复的参与配体结合的EGF样基序和3个拷贝的功能未知的Notch/lin-12基序。Notch的细胞内部分的特征在于被认为参与蛋白质-蛋白质相互作用的cdcl 0/锚蛋白基序的六个串联拷贝。在小鼠中已知四个Notch家族（Notch 1至Notch 4）成员。尽管Notch受体被配体家族如Delta激活，但它们也可以通过细胞外结构域的截短而被组成性激活。因为与人类T细胞急性淋巴细胞白血病亚群相关的染色体易位导致缺乏EGF样重复序列的截短Notch 1的过度表达。在小鼠乳腺肿瘤病毒（MMTV）诱导的乳腺肿瘤中，Notch 4类似截短形式作为致癌蛋白发挥作用。我们在这里报告频繁插入MMTV前病毒与LTR重排的Notch 1基因在胸腺瘤诱导这些MMTV LTR突变。MMTV前病毒插入导致Notch 1的细胞内部分的截短蛋白的表达。此外，在BALB/C小鼠自发性乳腺肿瘤中发现了Notch 4基因的胞浆内A颗粒（IAP），即小鼠反转录转座子插入。类似于上述Notch 1重排，IAP转座导致截短的Notch 4蛋白的过表达，所述截短的Notch 4蛋白由来自IAP gag序列的14个氨基酸组成，随后是Notch 4的胞质结构域。我们正在测试这些截短的Notch蛋白的转化活性。

The Notch gene family encodes a transmembrane receptor that controls cell fate decisions throughout development in Drosophila and vertebrate. The amino terminus of Notch proteins encodes the extra-cellular domain and contains as many as 36 repeats of EGF-like motif involved in ligand binding and three copies of Notch/lin-12 motif of unknown function. The intracellular portion of Notch is characterized by six tandem copies of cdcl0/ankyrin motif thought to be involved in protein-protein interaction. Four Notch family (Notch 1 to Notch 4) members are known in mouse. Although Notch receptors are activated by a family of ligands such as Delta, they may also be constitutively activated by truncation of the extracellular domain. Because chromo-somal translocation associated with a subset of human T cell acute lymphoblastic leukemias results in overexpression of truncated Notch 1 lacking the EGF-like repeats. Similar truncated form of Notch 4 function as oncogenic protein in mouse mammary tumor virus (MMTV) induced mammary tumor. We report here frequent insertions of MMTV proviruses with LTR rearrangement in the Notch 1 gene in the thymomas induced by these MMTV LTR mutants. MMTV provirus insertions resulted in expression of truncated proteins consist of intracellular part of Notch 1 .Furthermore intracytoplasmic A particle (IAP), a mouse retrotransposon insertion in the Notch 4 gene was found in a spontaneous mammary tumor in BALB/C mouse. Similar to Notch 1 rearrangement described above, IAP transposition led to overexpression of truncated Notch 4 protein composed of 14 amino acids from IAP gag sequence followed by the cytoplasmic domain of Notch 4. We are testing transformation activities of these truncated Notch proteins.