Grütz G G, Bucher K, Lavenir I, Larson T, Larson R, Rabbitts T H
MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK.
EMBO J. 1998 Aug 17;17(16):4594-605. doi: 10.1093/emboj/17.16.4594.
The LIM-only protein LMO2 is expressed aberrantly in acute T-cell leukaemias as a result of the chromosomal translocations t(11;14) (p13;q11) or t(7;11) (q35;p13). In a transgenic model of tumorigenesis by Lmo2, T-cell acute leukaemias arise after an asymptomatic phase in which an accumulation of immature CD4(-) CD8(-) double negative thymocytes occurs. Possible molecular mechanisms underlying these effects have been investigated in T cells from Lmo2 transgenic mice. Isolation of DNA-binding sites by CASTing and band shift assays demonstrates the presence of an oligomeric complex involving Lmo2 which can bind to a bipartite DNA motif comprising two E-box sequences approximately 10 bp apart, which is distinct from that found in erythroid cells. This complex occurs in T-cell tumours and it is restricted to the immature CD4(- )CD8(-) thymocyte subset in asymptomatic transgenic mice. Thus, ectopic expression of Lmo2 by transgenesis, or by chromosomal translocations in humans, may result in the aberrant protein interactions causing abnormal regulation of gene expression, resulting in a blockage of T-cell differentiation and providing precursor cells for overt tumour formation.
仅含LIM结构域的蛋白LMO2在急性T细胞白血病中异常表达，这是由染色体易位t(11;14)(p13;q11)或t(7;11)(q35;p13)所致。在Lmo2诱导的肿瘤发生转基因模型中，T细胞急性白血病在无症状期后出现，此期间会发生未成熟CD4(-)CD8(-)双阴性胸腺细胞的积累。已在Lmo2转基因小鼠的T细胞中研究了这些效应潜在的分子机制。通过CASTing和凝胶迁移实验分离DNA结合位点，结果表明存在一种涉及Lmo2的寡聚复合物，它能结合到一个由两个相距约10 bp的E-box序列组成的二分DNA基序上，这与在红系细胞中发现的基序不同。这种复合物存在于T细胞肿瘤中，且在无症状转基因小鼠中仅限于未成熟的CD4(-)CD8(-)胸腺细胞亚群。因此，通过转基因或人类染色体易位导致的Lmo2异位表达，可能会导致异常的蛋白质相互作用，引起基因表达的异常调控，从而导致T细胞分化受阻，并为明显的肿瘤形成提供前体细胞。
