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，该受体控制果蝇和脊椎动物在整个发育过程中的细胞命运决定。Notch蛋白的氨基末端编码胞外结构域，包含多达36个参与配体结合的EGF样基序和3个拷贝的未知功能的Notch/Lin-12基序。Notch的胞内部分由六个串联的cdcl0/ankyrin基序组成，被认为参与了蛋白质之间的相互作用。在鼠标中已知四个Notch家族成员(Notch 1到Notch 4)。虽然Notch受体被Delta等一系列配体激活，但它们也可能被细胞外结构域截断而被结构性激活。由于染色体易位与人类T细胞亚群相关，急性淋巴细胞性白血病导致截短的Notch 1过表达，缺乏EGF样重复。在小鼠乳腺肿瘤病毒(MMTV)诱导的乳腺肿瘤中，Notch 4的功能类似于癌基因蛋白。我们在此报告了在这些MMTV LTR突变体诱发的胸腺瘤中，在Notch 1基因中频繁插入带有LTR重排的MMTV前病毒。在BALB/C小鼠的自发性乳腺肿瘤中发现了Notch 4基因的小鼠反转录转座子插入。与上面描述的Notch 1重排类似，IAP转座导致由IAP Gag序列的14个氨基酸组成的截短的Notch 4蛋白的过表达，紧随其后的是Notch 4的细胞质结构域。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.