Two distinct Notch1 mutant alleles are involved in the induction of T-cell leukemia in c-myc transgenic mice
Two distinct Notch1 mutant alleles are involved in the induction of T-cell leukemia in c-myc transgenic mice
复制标题
DOI：
10.1128/mcb.20.11.3831-3842.2000
复制
发表时间：
2000-06-01
影响因子：
5.3
通讯作者：
Jolicoeur, P
中科院分区：
文献类型：
--
作者：
Hoemann, CD;Beaulieu, N;Jolicoeur, P
我们以前的特点是一个大面板的前病毒插入Notch 1突变等位基因和它们的产品中产生的胸腺瘤的MMTVD/myc转基因小鼠。是，我们表明，这些Notch 1突变代表两个明显不同的类。在第一类（I型）中，前病毒整合聚集在编码跨膜结构域的序列上游。I型Notch 1等位基因产生两种类型的突变Notch 1 RNA，其中一种编码整个Notch 1胞质结构域[N（IC）]，另一种编码可溶性胞外域[N（EC）（Mut）]，与加工的野生型胞外域[N（EC）（WT）]相比，其不驻留在细胞表面，并以温度依赖性方式分泌。第二类新的突变Notch 1等位基因（II型）编码C-末端PEST基序缺失的Notch 1受体（Delta CT）。II型Notch 1（Delta CT）蛋白在细胞表面表达为正常加工的受体[N（EC）（WT）和N（IC）（Delta CT）]，发现其胞外域以温度和钙依赖性方式脱落到细胞外介质中。这些数据表明，I型和II型突变产生两种结构不同的Notch 1 N（EC）和N（IC）蛋白，它们可能与c-myc癌基因合作，通过不同的机制参与肿瘤形成。组成型I型N（IC）和II型N（IC）（Delta CT）表达可以增强Notch 1细胞内信号传导，而分泌或脱落的I型N（EC）（Mut）和II型N（EC）蛋白可以以自分泌或旁分泌方式与Notch 1的配体差异地相互作用并影响它们的信号传导。
We have previously characterized a large panel of provirus insertion Notch1 mutant alleles and their products arising in thymomas of MMTVD/myc transgenic mice. Were, we show that these Notch1 mutations represent two clearly distinct classes. In the first class (type I), proviral integrations were clustered just upstream of sequences encoding the transmembrane domain. Type I Notch1 alleles produced two types of mutant Notch1 RNA, one of which encoded the entire Notch1 cytoplasmic domain [N(IC)] and the other of which encoded a soluble ctodomain [N(EC)(Mut)] which, in contrast to the processed wild-type ectodomain [N(EC)(WT)], did not reside at the cell surface and became secreted in a temperature-dependent manner. A second, novel class of mutant Notch1 allele (type II) encoded a Notch1 receptor with the C-terminal PEST motif deleted (Delta CT). The type II Notch1(Delta CT)protein was expressed as a normally processed receptor [N(EC)(WT) and N(IC)(Delta CT)] at the cell surface, and its ectodomain was found to be shed into the extracellular medium in a temperature- and calcium-dependent manner. These data suggest that both type I and type II mutations generate two structurally distinct Notch1 N(EC) and N(IC) proteins that may participate in tumor formation, in collaboration with the c-myc oncogene, through distinct mechanisms. Constitutive type I N(IC) and type II N(IC)(Delta CT) expression may enhance Notch1 intracellular signaling, while secreted or shed type I N(EC)(Mut) and type II N(EC) proteins may differentially interact in an autocrine or paracrine fashion with ligands of Notch1 and affect their signaling.