Takehana K, Sato S, Kobayasi T, Maeda T
Pharmaceutical Research Laboratories, Ajinomoto Co., Inc., 1-1 Suzuki-cho, Kawasaki-ku, Kawasaki 2, 10-0861, Japan.
Biochem Biophys Res Commun. 1999 Apr 2;257(1):19-23. doi: 10.1006/bbrc.1999.0401.
Macrocyclic nonaketide compounds, radicicol and its two analogues, 87-250904-F1 and LL-Z1640-2, have various biological activities. Here we show that these compounds inhibit signal-dependent transcriptional activation with different specificity with distinct mechanism. Although all three compounds inhibited PMA-induced AP-1 transcriptional activity in cell-based reporter assay, these compounds exhibited differential effects in separate transcriptional reporter assays for NF-kappaB and glucocorticoid receptor. Next we found that one of these compounds, LL-Z1640-2, was a signal-specific inhibitor of the JNK/p38 pathways. In contrast to LL-Z1640-2, radicicol and 87-250904-F1 did not inhibit JNK/p38 activation. Recently, radicicol was reported as an inhibitor of activated-Ras-induced ERK activation. These results indicated that radicicol and LL-Z1640-2 showed distinct specificity to various MAP kinase pathways despite their structural similarity. Furthermore, LL-Z-1640-2 inhibited anisomycin-induced but not TNF-induced JNK/p38 activation, indicating that the inhibition mechanism is signal-specific.
大环九酮类化合物、萝卜素及其两种类似物87 - 250904 - F1和LL - Z1640 - 2具有多种生物活性。在此我们表明，这些化合物通过不同的机制以不同的特异性抑制信号依赖性转录激活。尽管在基于细胞的报告基因检测中，这三种化合物均抑制佛波酯（PMA）诱导的AP - 1转录活性，但在针对核因子κB（NF - κB）和糖皮质激素受体的单独转录报告基因检测中，这些化合物表现出不同的效应。接下来我们发现，其中一种化合物LL - Z1640 - 2是JNK/p38信号通路的信号特异性抑制剂。与LL - Z1640 - 2不同，萝卜素和87 - 250904 - F1不抑制JNK/p38的激活。最近，萝卜素被报道为活化型Ras诱导的ERK激活的抑制剂。这些结果表明，尽管萝卜素和LL - Z1640 - 2结构相似，但它们对各种丝裂原活化蛋白激酶（MAP）信号通路表现出不同的特异性。此外，LL - Z - 1640 - 2抑制茴香霉素诱导的JNK/p38激活，但不抑制肿瘤坏死因子（TNF）诱导的JNK/p38激活，这表明其抑制机制具有信号特异性。
