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首页> 外文期刊>Journal of receptor and signal transduction research >Cyclic AMP-induced p53 destabilization is independent of EPAC in pre-B acute lymphoblastic leukemia cells in vitro
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Cyclic AMP-induced p53 destabilization is independent of EPAC in pre-B acute lymphoblastic leukemia cells in vitro

机译：循环AMP诱导的p53失稳独立于体外B前急性淋巴细胞白血病细胞中的EPAC

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Activation of the tumor suppressor protein p53 facilitates the cellular response to genotoxic stress. Thus, releasing the wild-type p53 from indirect suppression would be crucial to successful killing of cancer cells by DNA-damaging therapeutic agents. Objective: The aim of this study was to investigate the inhibitory role of cyclic adenosine monophosphate (cAMP) levels on p53 protein in acute lymphoblastic leukemia (ALL) cells. More importantly, we were interested to show through which receptor cAMP acts to promote p53 degradation. Materials and methods: In cell cultures, we investigated the effects of forskolin/3-isobutyl-1-methylxanthine (IBMX) on stimulated p53 of ALL cell lines. Western blotting analysis was performed to detect the expression of p53, phospho-p53, acetylated-p53, phospho-cAMP response element-binding protein (CREB), and Mdm2 proteins. Flow cytometry was applied to analyze apoptosis. The gene expression of p53 and its target genes was examined by real-time polymerase chain reaction. Results: We show that elevation of cAMP levels in ALL cells exposed to DNA damage attenuates p53 accumulation. Inhibition of proteosome function with MG-132 reversed the inhibitory effect of cAMP on p53. However, targeting the p53-Mdm2 interaction did not rescue accumulated p53 from the destabilizing signal of cAMP. The specific agonist of the cAMP receptor exchange protein activated by cAMP had no effect on p53 expression in doxorubicin-treated NALM-6 cells, whereas PKA activators decreased p53 accumulation. Discussion and conclusion: Our studies demonstrate that cAMP-PKA pathway regulates the sensitivity toward DNA-damaging agents via inhibition of a p53-dependent pathway in B-cell precursor ALL (BCP-ALL) cells.
机译：肿瘤抑制蛋白p53的激活促进了细胞对遗传毒性应激的反应。因此，从间接抑制中释放野生型p53对通过破坏DNA的治疗剂成功杀死癌细胞至关重要。目的：本研究旨在探讨环磷酸一腺苷（cAMP）水平对急性淋巴细胞白血病（ALL）细胞中p53蛋白的抑制作用。更重要的是，我们有兴趣展示cAMP通过哪种受体来促进p53降解。材料和方法：在细胞培养物中，我们研究了毛喉素/ 3-异丁基-1-甲基黄嘌呤（IBMX）对ALL细胞系受刺激的p53的作用。进行蛋白质印迹分析以检测p53，磷酸化p53，乙酰化的p53，磷酸化cAMP反应元件结合蛋白（CREB）和Mdm2蛋白的表达。流式细胞仪用于分析细胞凋亡。通过实时聚合酶链反应检查p53及其靶基因的基因表达。结果：我们表明，暴露于DNA损伤的ALL细胞中cAMP水平的升高会减弱p53的积累。用MG-132抑制蛋白体功能可逆转cAMP对p53的抑制作用。但是，靶向p53-Mdm2相互作用不能从cAMP的不稳定信号中挽救积累的p53。 cAMP激活的cAMP受体交换蛋白的特异性激动剂对阿霉素处理的NALM-6细胞中的p53表达没有影响，而PKA激活剂减少了p53的积累。讨论与结论：我们的研究表明，cAMP-PKA途径可通过抑制B细胞前体ALL（BCP-ALL）细胞中的p53依赖性途径来调节对DNA损伤剂的敏感性。

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