Basiliolides, a class of tetracyclic C19 dilactones from Thapsia garganica, release Ca2+ from the endoplasmic reticulum and regulate the activity of the transcription factors nuclear factor of activated T cells, nuclear factor-κB, and activator protein 1 in T lymphocytes
Basiliolides, a class of tetracyclic C19 dilactones from Thapsia garganica, release Ca2+ from the endoplasmic reticulum and regulate the activity of the transcription factors nuclear factor of activated T cells, nuclear factor-κB, and activator protein 1 in T lymphocytes
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DOI：
10.1124/jpet.106.108209
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发表时间：
2006-10-01
影响因子：
3.5
通讯作者：
Munoz, Eduardo
中科院分区：
文献类型：
--
作者：
Navarrete, Carmen;Sancho, Rocio;Munoz, Eduardo
内质网内钙离子浓度)在细胞生理学中起着重要作用。我们研究了从塔普西亚中分离得到的一类新的C19双内酯类化合物Basilioldes对T细胞内钙动员的影响。Basiliolide A1诱导白血病T细胞系Jurkat细胞内钙离子的快速动员。1，2-二(2-氨基苯氧基)乙烷-N，N，N‘，N’-四乙酸乙酰氧甲酯对钙离子有快速的抑制作用。在这种初始的钙动员之后，细胞外钙通过储存操作的钙释放激活的钙通道进入细胞内，并对EGTA和CRAC通道抑制剂N-{4-[3，5-双(三氟甲基)-1H吡唑基]phenyl}-4-methyl-1，2，3-thiadiazole-5-carboxamide(BTP-2)敏感。与thapsigargin不同，Basiliolide A1可从内质网储存库中动员钙离子，但不能诱导细胞凋亡。Basiliolide A1诱导活化的T细胞核因子1去磷酸化和活化，该作用可被BTP-2和环孢菌素A抑制。此外，我们发现Bsiliolide A1单独并不介导IKBα的降解或relA的磷酸化(Ser536)，但它与佛波醇12-肉豆蔻酸酯13-乙酸酯协同作用，诱导核因子-KB抑制蛋白的完全降解，并激活c-Jun NH2-末端的激酶。此外，Basiliolide A1在转录水平上调节IL-2和肿瘤坏死因子-α基因的表达。在担子内酯B中，两个双子甲基中的一个氧化成羧甲基团保留了担子内酯A1的大部分活性。相比之下，15-碳被氧化成乙酰氧亚胺的巴里内酯C的活性要低得多。这些发现使这些化合物有资格成为研究细胞内钙稳态的新探针。
Calcium concentration within the endoplasmic reticulum ER) plays an essential role in cell physiology. We have investigated the effects of basiliolides, a novel class of C19 dilactones isolated from Thapsia garganica, on Ca2+ mobilization in T cells. Basiliolide A1 induced a rapid mobilization of intracellular Ca2+ in the leukemia T-cell line Jurkat. First, a rapid calcium peak was observed and inhibited by 1,2-bis(2-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester. This initial calcium mobilization was followed by a sustained elevation, mediated by the entry of extracellular calcium through store-operated calcium release-activated Ca2+ (CRAC) channels and sensitive to inhibition by EGTA, and by the CRAC channel inhibitor N-{4-[3,5-bis(trifluoromethyl)-1Hpyrazol1-yl] phenyl}-4-methyl-1,2,3-thiadiazole-5-carboxamide (BTP-2). Basiliolide A1 mobilized Ca2+ from ER stores, but in contrast to thapsigargin, it did not induce apoptosis. Basiliolide A1 induced nuclear factor of activated T cells 1 dephosphorylation and activation that was inhibited by BTP-2 and cyclosporine A. In addition, we found that basiliolide A1 alone did not mediate IKB alpha degradation or RelA phosphorylation (ser536), but it synergized with phorbol 12-myristate 13-acetate to induce a complete degradation of the nuclear factor-KB inhibitory protein and to activate the c-Jun NH2-terminal kinase. Moreover, basiliolide A1 regulated both interleukin-2 and tumor necrosis factor-alpha gene expression at the transcriptional level. In basiliolide B, oxidation of one of the two geminal methyls to a carboxymethyl group retained most of the activity of basiliolide A1. In contrast, basiliolide C, where the 15-carbon is oxidized to an acetoxymethine, was much less active. These findings qualify these compounds as new probes to investigate intracellular calcium homeostasis.