NOTCH1 t(7;9)(NOTCH1:M1580_K2555) 转位突变体的持续信号传导
中文名称
通路描述
NOTCH1 t(7;9)(NOTCH1:M1580_K2555) 突变体在 T 细胞急性淋巴细胞白血病（T-ALL）患者的小部分中表达。该突变蛋白是通过 NOTCH1 基因内含子 24 的一部分与 T 细胞受体β（TCRB）的启动子序列之间的转位而形成的，导致 T 细胞及其前体中截短 NOTCH1 蛋白的过表达。截短的 NOTCH1 包含野生型 NOTCH1 的氨基酸 1580 至 2555，几乎缺少整个细胞外结构域，包括 EGF 和 LIN12 重复序列（Ellisen 等，1991）。由于 EGF 重复对于 NOTCH1 与其配体（DLL1、DLL4、JAG1、JAG2）的相互作用是必需的，因此突变 NOTCH1 t(7;9)(NOTCH1:M1580_K2555) 不结合配体。NOTCH1 t(7;9)(NOTCH1:M1580_K2555) 的持续活性基于其由 ADAM10/17 蛋白酶和γ-分泌酶复合物进行持续蛋白水解加工为 NOTCH1 细胞内结构域（NICD1），因为突变蛋白中缺乏配体结合时暴露了蛋白水解切割位点。持续产生的 NICD1 积累在细胞核中，导致 NOTCH1 靶基因的异常激活，这些靶基因在 T 淋巴细胞的发展中起着重要作用（Washburn 等，1997；Radtke 等，1999；Maillard 等，2004；Sambandam 等，2005；Tan 等，2005）。将编码截短 NOTCH1 的重组逆转录病毒感染的骨髓细胞导致部分小鼠获得 T-ALL 样疾病，所有肿瘤均表达截短的 NOTCH1 形式（Pear 等，1996）。
英文描述
Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant NOTCH1 t(7;9)(NOTCH1:M1580_K2555) mutant is expressed in a small subset of T-cell acute lymphoblastic leukemia (T-ALL) patients. This mutant protein results from a translocation that joins a portion of intron 24 of the NOTCH1 gene to the promoter sequence of T-cell receptor beta (TCRB), leading to overexpression of a truncated NOTCH1 protein in T-cells and their precursors. The truncated NOTCH1 contains amino acids 1580 to 2555 of the wild-type NOTCH1, lacking almost the entire extracellular domain, including EGF and LIN12 repeats (Ellisen et al. 1991). As EGF repeats are needed for NOTCH1 interaction with its ligands (DLL1, DLL4, JAG1, JAG2), the mutant NOTCH1 t(7;9)(NOTCH1:M1580_K2555) does not bind a ligand. The constitutive activity of NOTCH1 t(7;9)(NOTCH1:M1580_K2555) is based on its constitutive proteolytic processing into NOTCH1 intracellular domain (NICD1) by ADAM10/17 protease and gamma-secretase complex, as proteolytic cleavage sites are exposed in the absence of ligand binding in the mutant protein. Constitutively produced NICD1 accumulates in the nucleus, leading to aberrant activation of NOTCH1 target genes which play important roles in the development of T lymphocytes (Washburn et al. 1997. Radtke et al. 1999, Maillard et al. 2004, Sambandam et al. 2005, Tan et al. 2005). Infection of bone marrow cells with recombinant retroviruses that code for truncated NOTCH1 that resembles t(7;9)(NOTCH1:M1580_K2555) resulted in T-ALL-like illness in a portion of mice that received the infected bone-marrow transplant, with all tumors overexpressing truncated forms of NOTCH1 (Pear et al. 1996).
所含基因
8 个基因