Aziz-Aloya R B, Levanon D, Karn H, Kidron D, Goldenberg D, Lotem J, Polak-Chaklon S, Groner Y
Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot, 76100 Israel.
Cell Death Differ. 1998 Sep;5(9):765-73. doi: 10.1038/sj.cdd.4400415.
The human AML1 gene encodes a heterodimeric transcription factor which plays an important role in mammalian hematopoiesis. Several alternatively spliced AML1 mRNA species were identified, some of which encode short protein products that lack the transactivation domain. When transfected into cells these short isoforms dominantly suppress transactivation mediated by the full length AML1 protein. However, their biological function remains obscure. To investigate the role of these short species in cell proliferation and differentiation we generated embryonic stem (ES) cells overexpressing one of the short isoforms, AML1-d, as well as cells expressing the full length isoforms AML1-b and AML2. The in vitro growth rate and differentiation of the transfected ES cells were unchanged. However, overexpression of AML1-d significantly affected the ES cells' ability to form teratocarcinomas in vivo in syngeneic mice, while a similar overexpression of AML1-b and AML2 had no effect on tumor formation. Histological analysis revealed that the AML1-d derived tumors were poorly differentiated and contained numerous apoptotic cells. These data highlight the pleiotropic effects of AML1 gene products and demonstrate for the first time an in vivo growth regulation function for the short isoform AML1-d.
人类AML1基因编码一种异二聚体转录因子，它在哺乳动物造血过程中发挥重要作用。已鉴定出几种选择性剪接的AML1 mRNA种类，其中一些编码缺少反式激活结构域的短蛋白产物。当转染到细胞中时，这些短异构体可显著抑制全长AML1蛋白介导的反式激活。然而，它们的生物学功能仍不清楚。为了研究这些短异构体在细胞增殖和分化中的作用，我们构建了过表达其中一种短异构体AML1-d的胚胎干细胞（ES细胞），以及表达全长异构体AML1-b和AML2的细胞。转染后的ES细胞的体外生长速率和分化未发生改变。然而，AML1-d的过表达显著影响了ES细胞在同基因小鼠体内形成畸胎瘤的能力，而AML1-b和AML2的类似过表达对肿瘤形成没有影响。组织学分析显示，源自AML1-d的肿瘤分化不良，含有大量凋亡细胞。这些数据突出了AML1基因产物的多效性作用，并首次证明了短异构体AML1-d在体内的生长调节功能。
