Transcriptional regulatory effects of lymphoma-associated NFKB2/lyt10 protooncogenes
Transcriptional regulatory effects of lymphoma-associated NFKB2/lyt10 protooncogenes
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DOI：
10.1038/sj.onc.1203432
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发表时间：
2000-03-02
期刊：
影响因子：
8
通讯作者：
Rabson, AB
中科院分区：
文献类型：
--
作者：
Kim, KE;Gu, CY;Rabson, AB
在许多人类皮肤T细胞淋巴瘤、人类b细胞淋巴瘤和骨髓瘤病例中，已经观察到NFKB2 p100基因产物的c端截断，这些改变对淋巴瘤发生的贡献尚不清楚；然而，在HUT78细胞系中，截断氨基酸666以产生80-85 kh)蛋白与p80HT 3'端添加短（丝氨酸-谷氨酸-丝氨酸）融合以及NFKB2 mRNA表达增加有关。因此，我们研究了p80HT对NFKB2表达调控的影响，以及NFKB2一系列其他肿瘤相关和位点定向突变的特性。虽然p80HT本身没有获得关于NFKB2 Pt或P2启动子或IL-6 kappa B启动子的新的转录激活特性，但p80HT已经失去了与野生型p100基因产物相关的强效抑制（I kappa B样）活性。抑制性能的丧失取决于融合蛋白中的SAS残基，在aa666处直接截断是完全抑制的，用三个丙氨酸取代SAS残基也是完全抑制的。仅两个c端锚蛋白基序的存在就足以抑制NF-kappa B介导的转录激活，对一系列其他淋巴瘤相关NF-kappa B-2截断的分析表明，与这些蛋白相关的c端截断也与p100 NF-kappa B-2的I -kappa B样活性的丧失有关，至少对一些NF-kappa B靶启动子而言。因此，淋巴瘤相关NFKB2突变I κ b样活性的丧失可能在人类淋巴瘤亚群的发生中起重要作用。
C-terminal truncations of the NFKB2 p100 gene product have been observed in a number of cases of human cutaneous T cell lymphomas, as well as human B-cell lymphomas and myelomas, The contribution of these alterations to lymphomagenesis is not understood; however, truncation at amino acid 666 to generate 80-85 kh) proteins in the HUT78 cell line is associated with addition of a short (serine-alanine-serine) fusion at the 3' end of p80HT, as well as with increased expression of NFKB2 mRNA, We therefore examined the effects of p80HT on the regulation of NFKB2 expression, as well ms the properties of a series of other tumor-associated, and site directed mutations of NFKB2, While p80HT had not itself acquired novel transcriptional activation properties with respect to the NFKB2 Pt or P2 promoters or the IL-6 kappa B promoter, p80HT had lost tate potent inhibitory (I kappa B-like) activity associated with the wild-type, p100 gene product. Loss of the inhibitory property depended on the SAS residues in the fusion protein, direct truncation at aa666 was fully inhibitory, as was a substitution of three alanines for the SAS residues. The presence of as few as two C-terminal ankyrin motifs was sufficient for inhibition of NF-kappa B-mediated transcriptional activation, Assays of a series of additional lymphoma-associated NF-kappa B-2 truncation suggested that the C-terminal truncation associated with these proteins was also associated with a loss of the I kappa B-like activities of p100 NF-kappa B-2, for at least some NF-kappa B target promoters. Thus, the loss of I kappa B-like activity of lymphoma-associated NFKB2 mutations may play an important role in the genesis of a subset of human lymphomas.