De Vivo I, Cui X, Domen J, Cleary M L
Department of Pathology, Stanford University Medical Center, Stanford, CA 94305, USA.
Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9471-6. doi: 10.1073/pnas.95.16.9471.
SET binding factor 1 (Sbf1) was originally discovered by virtue of its interaction with a highly conserved motif (the SET domain) of unknown function in the protooncoprotein homolog of Drosophila trithorax, Hrx. Sbf1 shares extensive sequence similarity with myotubularin, a dual specificity phosphatase (dsPTPase) that is mutated in a subset of patients with inherited myopathies. Both Sbf1 and myotubularin interact with the SET domains of Hrx and other epigenetic regulatory proteins, but Sbf1 lacks phosphatase activity due to several evolutionarily conserved amino acid changes in its structurally preserved catalytic pocket. Thus, Sbf1 has features of an anti-phosphatase that could competitively antagonize dsPTPases; however the in vivo role for such factors remains unknown. Given its ability to physically interact with Hrx, a developmental regulator subject to translocation-induced mutations in B cell precursor leukemias, the current studies were undertaken to assess the effects of Sbf1 on lymphopoiesis. After infection with recombinant Sbf1 retroviruses, bone marrow cells were plated under Whitlock-Witte conditions for long-term culture of B lineage cells. Sbf1-expressing cells rapidly dominated the cultures resulting in clonal outgrowths of B cell progenitors that retained a dependence on their primary bone marrow-derived stroma for continuous growth in vitro. Structure/function analyses demonstrated that the SET interaction domain of Sbf1 was necessary and sufficient for growth alterations of B cell progenitors. These observations support a model in which Sbf1 functions as a SET domain-dependent positive regulator of growth-inducing kinase signaling pathways that impinge on SET domain proteins. SET domain-dsPTPase interactions appear to be critically important for regulating the growth properties of B cell progenitors.
SET结合因子1（Sbf1）最初是因其与果蝇三体胸蛋白同源原癌蛋白Hrx中一个功能未知的高度保守基序（SET结构域）相互作用而被发现的。Sbf1与肌管素具有广泛的序列相似性，肌管素是一种双特异性磷酸酶（dsPTPase），在一部分遗传性肌病患者中发生了突变。Sbf1和肌管素都与Hrx及其他表观遗传调节蛋白的SET结构域相互作用，但由于其结构保守的催化口袋中存在几个进化上保守的氨基酸变化，Sbf1缺乏磷酸酶活性。因此，Sbf1具有抗磷酸酶的特征，可竞争性拮抗dsPTPases；然而，此类因子在体内的作用仍不清楚。鉴于其能够与Hrx发生物理相互作用，Hrx是一种发育调节因子，在B细胞前体白血病中会发生易位诱导的突变，因此开展了当前的研究以评估Sbf1对淋巴细胞生成的影响。用重组Sbf1逆转录病毒感染后，将骨髓细胞接种在Whitlock-Witte条件下，用于B系细胞的长期培养。表达Sbf1的细胞迅速在培养物中占主导地位，导致B细胞祖细胞的克隆性生长，这些祖细胞在体外持续生长仍依赖于其原始骨髓来源的基质。结构/功能分析表明，Sbf1的SET相互作用结构域对于B细胞祖细胞的生长改变是必要且充分的。这些观察结果支持了一个模型，即Sbf1作为一种依赖SET结构域的生长诱导激酶信号通路的正向调节因子，作用于SET结构域蛋白。SET结构域与dsPTPase的相互作用似乎对于调节B细胞祖细胞的生长特性至关重要。
