Tanaka T, Tanaka K, Ogawa S, Kurokawa M, Mitani K, Nishida J, Shibata Y, Yazaki Y, Hirai H
Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
EMBO J. 1995 Jan 16;14(2):341-50. doi: 10.1002/j.1460-2075.1995.tb07008.x.
The AML1 gene on chromosome 21 is disrupted in the (8;21)(q22;q22) and (3;21)(q26;q22) translocations associated with myelogenous leukemias and encodes a DNA binding protein. From the AML1 gene, two representative forms of proteins, AML1a and AML1b, are produced by alternative splicing. Both forms have a DNA binding domain but, unlike AML1b, AML1a lacks a putative transcriptional activation domain. Here we demonstrate that overexpressed AML1a totally suppresses granulocytic differentiation and stimulates cell proliferation in 32Dcl3 murine myeloid cells treated with granulocyte colony-stimulating factor. These effects of AML1a were canceled by the concomitant overexpression of AML1b. Such biological phenomena could be explained by our observations that (i) AML1a, which on its own has no effects as a transcriptional regulator, dominantly suppresses transcriptional activation by AML1b, and (ii) AML1a exhibits the higher affinity for DNA binding compared with AML1b. These antagonistic actions could be important in leukemogenesis and/or myeloid cell differentiation because more than half of myelogenous leukemia patients showed an increase in the relative amounts of AML1a.
21号染色体上的AML1基因在与骨髓性白血病相关的(8;21)(q22;q22)和(3;21)(q26;q22)易位中发生破坏，并编码一种DNA结合蛋白。从AML1基因中，通过可变剪接产生两种代表性的蛋白质形式，AML1a和AML1b。两种形式都有一个DNA结合结构域，但与AML1b不同，AML1a缺乏一个假定的转录激活结构域。在这里，我们证明，在用粒细胞集落刺激因子处理的32Dcl3小鼠骨髓细胞中，过表达的AML1a完全抑制粒细胞分化并刺激细胞增殖。AML1a的这些作用被AML1b的同时过表达所抵消。这种生物学现象可以通过我们的观察来解释：(i) AML1a本身作为转录调节因子没有作用，但能显著抑制AML1b的转录激活；(ii)与AML1b相比，AML1a对DNA结合表现出更高的亲和力。这些拮抗作用在白血病发生和/或骨髓细胞分化中可能很重要，因为超过一半的骨髓性白血病患者显示AML1a的相对量增加。
