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首页> 外文期刊>Molecular and Cellular Biology >Induction of bcl-2 expression by phosphorylated CREB proteins during B-cell activation and rescue from apoptosis.
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Induction of bcl-2 expression by phosphorylated CREB proteins during B-cell activation and rescue from apoptosis.

机译：磷酸化的CREB蛋白在B细胞活化和细胞凋亡拯救过程中诱导bcl-2表达。

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Engagement of surface immunoglobulin on mature B cells leads to rescue from apoptosis and to proliferation. Levels of bcl-2 mRNA and protein increase with cross-linking of surface immunoglobulin. We have located the major positive regulatory region for control of bcl-2 expression in B cells in the 5'-flanking region. The positive region can be divided into an upstream and a downstream regulatory region. The downstream regulatory region contains a cyclic AMP-responsive element (CRE). We show by antibody supershift experiments and UV cross-linking followed by denaturing polyacrylamide gel electrophoresis that both CREB and ATF family members bind to this region in vitro. Mutations of the CRE site that result in loss of CREB binding also lead to loss of functional activity of the bcl-2 promoter in transient-transfection assays. The presence of an active CRE site in the bcl-2 promoter implies that the regulation of bcl-2 expression is linked to a signal transduction pathway in B cells. Treatment of the mature B-cell line BAL-17 with either anti-immunoglobulin M or phorbol 12-myristate 13-acetate leads to an increase in bcl-2 expression that is mediated by the CRE site. Treatment of the more immature B-cell line, Ramos, with phorbol esters rescues the cells from calcium-dependent apoptosis. bcl-2 expression is increased following phorbol ester treatment, and the increased expression is dependent on the CRE site. These stimuli result in phosphorylation of CREB at serine 133. The phosphorylation of CREB that results in activation is mediated by protein kinase C rather than by protein kinase A. Although the CRE site is necessary, optimal induction of bcl-2 expression requires participation of the upstream regulatory element, suggesting that phosphorylation of CREB alters its interaction with the upstream regulatory element. The CRE site in the bcl-2 promoter appears to play a major role in the induction of bcl-2 expression during the activation of mature B cells and during the rescue of immature B cells from apoptosis. It is possible that the CRE site is responsible for induction of bcl-2 expression in other cell types, particularly those in which protein kinase C is involved.
机译：表面免疫球蛋白与成熟B细胞的结合导致细胞凋亡和增殖的恢复。 bcl-2 mRNA和蛋白的水平随着表面免疫球蛋白的交联而增加。我们在5'侧翼区域定位了B细胞中bcl-2表达控制的主要阳性调控区域。正区域可分为上游和下游调节区域。下游调节区包含一个环状AMP响应元件（CRE）。我们通过抗体超位移实验和UV交联展示了变性聚丙烯酰胺凝胶电泳，表明CREB和ATF家族成员均在体外与该区域结合。在瞬时转染测定中，导致CREB结合丧失的CRE位点突变也导致bcl-2启动子的功能活性丧失。 bcl-2启动子中存在活跃的CRE位点意味着bcl-2表达的调节与B细胞中的信号转导途径相关。用抗免疫球蛋白M或佛波醇12-肉豆蔻酸酯13-乙酸酯处理成熟的B细胞系BAL-17导致由CRE位点介导的bcl-2表达增加。用佛波醇酯处理更不成熟的B细胞系Ramos可以使细胞摆脱钙依赖性细胞凋亡。佛波酯处理后bcl-2表达增加，并且表达增加取决于CRE位点。这些刺激导致丝氨酸133处的CREB磷酸化。导致激活的CREB的磷酸化是由蛋白激酶C而不是由蛋白激酶A介导的。尽管CRE位点是必需的，但bcl-2表达的最佳诱导仍需参与。上游调节元件，表明CREB的磷酸化改变了其与上游调节元件的相互作用。 bcl-2启动子中的CRE位点在激活成熟B细胞和挽救未成熟B细胞凋亡过程中似乎在bcl-2表达的诱导中起主要作用。 CRE位点可能负责诱导其他细胞类型中bcl-2表达，尤其是涉及蛋白激酶C的细胞。

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