BLOCKING OF TUMOR PROMOTER-INDUCED AP-1 ACTIVITY INHIBITS INDUCED TRANSFORMATION IN JB6 MOUSE EPIDERMAL-CELLS
BLOCKING OF TUMOR PROMOTER-INDUCED AP-1 ACTIVITY INHIBITS INDUCED TRANSFORMATION IN JB6 MOUSE EPIDERMAL-CELLS
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DOI：
10.1073/pnas.91.2.609
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发表时间：
1994-01-18
影响因子：
11.1
通讯作者：
COLBURN, NH
中科院分区：
文献类型：
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作者：
DONG, ZG;BIRRER, MJ;COLBURN, NH
AP-1转录活性在启动子敏感（pf）但在启动子抗性（P-）JB 6小鼠表皮细胞系中受转化启动子佛波醇12-肉豆蔻酸酯13-乙酸酯（“12-0-十四烷酰基佛波醇13乙酸酯，”TPA）和表皮生长因子（EGF）刺激。虽然TPA刺激jun和fos家族基因的表达，但只有c-jun表达在P+细胞中比在P-细胞中显示出更高的升高。本研究测试的假设，诱导AP-1活性是肿瘤启动子诱导的转化所需的JB 6 P+细胞。视黄酸和糖皮质激素氟轻松都能抑制基础和TPA诱导的AP-1活性，这些活性在P+细胞中用溶基质素启动子-氯霉素乙酰转移酶报告基因进行了测试。由于视黄酸和醋酸氟轻松在阻断TPA诱导的AP-1活性的剂量范围内抑制TPA诱导的P+细胞的锚定非依赖性转化，因此它们的抗促进作用可能通过抑制AP-1活性而发生。为了用更特异的抑制剂来检验该假设，分析了表达编码转录失活产物的显性负性c-jun突变体的P+细胞的稳定克隆转染子。所有转染子均显示TPA和EGF诱导AP-1活性的阻断。Ah转染子也表现出抑制TPA诱导的转化，并且大多数转染子表现出对EGF诱导的转化的阻断。这些结果表明，AP-1活性是TPA或EGF诱导的转化所必需的。这项工作表明，诱导的AP-1活性的特异性阻断抑制肿瘤启动子诱导的转化。
AP-1 transcriptional activity is stimulated by the transformation promoters phorbol 12-myristate 13-acetate (''12-0-tetradecanoyIphorbol 13 acetate,'' TPA) and epidermal growth factor (EGF) in promotion-sensitive (pf) but not in promotion-resistant (P-) JB6 mouse epidermal cell lines. Although TPA stimulates expression of the jun and fos family genes, only c-jun expression shows higher elevation in P+ cells than in P- cells. The present study tests the hypothesis that induced AP-1 activity is required for tumor promoter induced transformation in JB6 P+ cells. Both retinoic acid and the glucocorticoid fluocinolone acetonide inhibited basal and TPA-induced AP-1 activities that were tested with a stromelysin promoter-chloramphenicol acetyltransferase reporter gene in P+ cells. Since both retinoic acid and fluocinolone acetonide are active in inhibiting TPA-induced anchorage-independent transformation of P+ cells in the dose range that blocks TPA-induced AP-1 activity, their antipromoting effects may occur through inhibition of AP-1 activity. To test the hypothesis with a more specific inhibitor, stable clonal transfectants of P+ cells expressing dominant negative c-jun mutant encoding a transcriptionally inactive product were analyzed. All transfectants showed a block in TPA and EGF induction of AP-1 activity. Ah transfectants also showed inhibition of TPA-induced transformation, and most transfectants showed a block in EGF-induced transformation. These results indicate that AP-1 activity is required for TPA- or EGF-induced transformation. This work demonstrates that a specific block in induced AP-I activity inhibits tumor promoter-induced transformation.