TLS/FUS fusion domain of TLS/FUS-erg chimeric protein resulting from the t(16;21) chromosomal translocation in human myeloid leukemia functions as a transcriptional activation domain.
TLS/FUS fusion domain of TLS/FUS-erg chimeric protein resulting from the t(16;21) chromosomal translocation in human myeloid leukemia functions as a transcriptional activation domain.
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发表时间：
1994-12
期刊：
影响因子：
8
通讯作者：
D. Prasad;M. Ouchida;L. T. Lee;V. Rao;E. Reddy
中科院分区：
文献类型：
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作者：
D. Prasad;M. Ouchida;L. T. Lee;V. Rao;E. Reddy
编码RNA结合蛋白的EWS和TLS/FUS基因与多种人类实体肿瘤有关。TLS/FUS基因与携带特征性染色体易位的人黏液样脂肪肉瘤t(12;16)（q13;p11）和复发性染色体易位的人髓系白血病t(16;21)（p11:q22）有关。TLS/FUS基因与转录抑制因子CHOP（在人黏液样脂肪肉瘤中）或转录激活因子erg（在人髓性白血病中）融合。为了更好地了解TLS/FUS-erg在人髓性白血病中的功能作用，我们克隆了TLS/FUS和TLS/FUS-erg cdna，并研究了它们的基因产物的功能特性。TLS/FUS蛋白在体外与RNA结合，并表现出对聚G的优先结合。含有保守RNA结合基序的氨基端和羧基端区域是TLS/FUS蛋白具有聚G特异性RNA结合活性的必要条件。TLS/FUS融合结构域（TFD）调控了TLS/FUS-erg嵌合蛋白的DNA结合活性，与正常erg蛋白相比，其转录激活特性较弱。对TLS/FUS-erg嵌合蛋白的突变分析表明，TFD作为一个转录激活域，从而取代了erg蛋白的氨基端转录激活域。因此，异常erg蛋白的DNA结合和转录激活特性的改变可能是导致t（16;21）染色体易位的人髓性白血病发生的原因。
EWS and TLS/FUS genes, which code for RNA binding proteins are involved in a wide variety of human solid tumors. The TLS/FUS gene is involved both in human myxoid liposarcomas which carry a characteristic chromosomal translocation, t(12;16)(q13;p11) and in human myeloid leukemias with recurrent chromosomal translocation, t(16;21)(p11:q22). The TLS/FUS gene is fused to a transcriptional repressor, CHOP (in human myxoid liposarcomas) or transcriptional activator, erg (in human myeloid leukemias). To understand better the functional role of TLS/FUS-erg in human myeloid leukemias, we have cloned the TLS/FUS and TLS/FUS-erg cDNAs and studied the functional properties of their gene products. TLS/FUS protein binds to RNA in vitro and shows preferential binding to poly G. Both the amino- and the carboxy- terminal regions of TLS/FUS containing the conserved RNA binding motifs are needed for poly G specific RNA binding activity. The TLS/FUS fusion domain (TFD) appears to regulate the DNA binding activity of TLS/FUS-erg chimeric protein which shows weaker transcriptional activation properties compared to normal erg proteins. Mutational analysis of the TLS/FUS-erg chimeric protein reveals TFD to function as a transcriptional activation domain thus replacing the amino terminal transcriptional activation domain of the erg protein. Therefore alterations in both DNA binding and transcriptional activation properties of aberrant erg proteins may be responsible for the genesis of t(16;21) chromosomal translocation-bearing human myeloid leukemias.