AN ACTIVE V-ABL PROTEIN-TYROSINE KINASE BLOCKS IMMUNOGLOBULIN LIGHT-CHAIN GENE REARRANGEMENT
AN ACTIVE V-ABL PROTEIN-TYROSINE KINASE BLOCKS IMMUNOGLOBULIN LIGHT-CHAIN GENE REARRANGEMENT
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DOI：
10.1101/gad.8.6.688
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发表时间：
1994-03-15
影响因子：
10.5
通讯作者：
ROSENBERG, N
中科院分区：
文献类型：
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作者：
CHEN, YY;WANG, LC;ROSENBERG, N
Abelson鼠白血病病毒转化的淋巴细胞为研究早期B细胞发育和免疫球蛋白重排提供了经典模型之一。这些细胞中的大多数已经重新排列了它们的重链基因座，但没有重新排列了它们的轻链基因，这表明活性 v-abl 蛋白干扰了这一分化步骤。为了检验这一假设，我们对由 Abelson 病毒温度敏感突变体转化的前 B 细胞以及由于表达人类 BCL-2 基因而在非允许温度下存活的衍生物中的轻链基因结构进行了检查。我们的研究表明，v-abl 蛋白酪氨酸激酶失活会触发 kappa 和 lambda 轻链基因的高频重排。这些事件伴随着 RAG-1 和 RAG-2 RNA 表达的显着增加。这些增加发生在没有蛋白质合成的情况下，但依赖于 v-abl 蛋白酪氨酸激酶的失活。正如随附论文（Klug 等人，本期）所述，活性 v-abl 蛋白还会抑制 NF-kappaB/rel 的活性以及由 kappa 内含子增强子控制的表达。这些数据共同表明，v-abl 蛋白通过抑制 B 细胞分化这一阶段所必需的至少两条途径来特异性干扰轻链基因重排，并表明酪氨酸磷酸化在调节 RAG 基因表达中很重要。
Lymphoid cells transformed by Abelson murine leukemia virus have provided one of the classic models for study of early B-cell development and immunoglobulin rearrangement. Most of these cells have rearranged their heavy-chain locus but not their light chain genes, suggesting that an active v-abl protein interferes with this differentiation step. To test this hypothesis, light-chain gene structure was examined in pre-B cells transformed by temperature-sensitive mutants of the Abelson virus and in derivatives that survive at the nonpermissive temperature because they express a human BCL-2 gene. Our studies reveal that inactivation of the v-abl protein tyrosine kinase triggers high-frequency rearrangement of kappa and lambda light-chain genes. These events are accompanied by marked increases in the expression of RAG-1 and RAG-2 RNAs. These increases occur in the absence of protein synthesis but are dependent on inactivation of the v-abl protein tyrosine kinase. As documented in the accompanying paper (Klug et al., this issue), an active v-abl protein also suppresses the activity of NF-kappaB/rel and expression controlled by the kappa intron enhancer. Together these data demonstrate that the v-abl protein specifically interferes with light-chain gene rearrangement by suppressing at least two pathways essential for this stage of B-cell differentiation and suggest that tyrosine phosphorylation is important in regulating RAG gene expression.