The mouse mammary tumor associated gene INT3 is a unique member of the NOTCH gene family (NOTCH4)
The mouse mammary tumor associated gene INT3 is a unique member of the NOTCH gene family (NOTCH4)
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DOI：
10.1038/sj.onc.1201035
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发表时间：
1997-04-24
期刊：
影响因子：
8
通讯作者：
Callahan, R
中科院分区：
文献类型：
--
作者：
Gallahan, D;Callahan, R
INT 3基因在小鼠乳腺肿瘤病毒（MMTV）诱导的捷克Ⅱ系小鼠乳腺肿瘤中经常发生重排。我们已完成了正常的6.5Kb INT 3 RNA的核苷酸序列，并确定了该基因的内含子/外显子边界。INT 3 RNA的开放阅读框应编码一个200 kd的蛋白质，与果蝇NOTCH的小鼠同源物有60%的同源性。INT 3在NOTCH家族的其他成员中是独特的，在基因产物的细胞外结构域中含有29个而不是36个EGF样重复序列。五个新的EGF样重复序列已被创建为在进化过程中细胞外结构域的编码区内发生的明显的小缺失的结果。对来自9个独立的含有重排的INT 3基因的MMT诱导的乳腺肿瘤的宿主-病毒连接片段的核苷酸序列分析揭示，所有整合事件都发生在INT 3胞外结构域中编码LIN 12重复序列的3'和编码跨膜结构域的序列的5'的174 bp区域内。因此，由MMTV前病毒插入引起的唯一致瘤性INT 3突变是导致细胞内结构域表达的那些突变。这强烈表明，MMT诱导的INT 3活化在胞外结构域（包括LIN 12重复序列）的调节作用不存在的情况下是明显的，使表达的胞内结构域组成性地自由发挥其在乳腺肿瘤发生中的作用。
The INT3 gene is frequently rearranged in mouse mammary tumor virus (MMTV)-induced mammary tumors of the CzechII mouse strain, We have completed the nucleotide sequence of the normal 6.5 Kb INT3 RNA and defined the intron/exon boundaries of the gene, The open reading frame of INT3 RNA should encode a 200 kd protein which shares 60% homology with the mouse homologue of Drosophila NOTCH, INT3 is unique among other members of the NOTCH family by containing 29 instead of 36 EGF-like repeats in the extracellular domain of the gene product. Five novel EGF-like repeats have been created as consequence of apparent small deletions which have occurred within the coding region for the extracellular domain during evolution. Nucleotide sequence analysis of host-viral junction fragments from nine independent MMTV-induced mammary tumors containing a rearranged INT3 gene reveals that all of the integration events occur within a 174 bp region 3' of the sequences encoding the LIN12 repeats in the INT3 extracellular domain and 5' of the sequences encoding the transmembrane domain. Therefore, the only tumorigenic INT3 mutations resulting from MMTV proviral insertions are those which results in the expression of the intracellular domain. This strongly suggests that MMTV-induced activation of INT3 is manifest in the absence of the regulatory action of the extracellular domain, including the LIN12 repeat sequences, leaving the expressed intracellular domain constitutively free to function in its role in mammary tumorigenesis.