AP-1, NF-kappa-B, and ERK activation thresholds for promotion of neoplastic transformation in the mouse epidermal JB6 model.
AP-1, NF-kappa-B, and ERK activation thresholds for promotion of neoplastic transformation in the mouse epidermal JB6 model.
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DOI：
10.1289/ehp.02110865
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发表时间：
2002-09
影响因子：
10.4
通讯作者：
Colburn NH
中科院分区：
文献类型：
--
作者：
Suzukawa K;Weber TJ;Colburn NH
促进敏感的小鼠表皮JB 6细胞（克隆41）已被用于鉴定各种化合物的肿瘤促进活性。由于肿瘤促进剂[12-O-十四烷酰基佛波醇-13-乙酸酯（TPA）、表皮生长因子（EGF）或肿瘤坏死因子α（TNF-α）]的治疗将克隆41细胞转化为锚定非依赖性和致瘤表型，因此认为它们正在经历晚期肿瘤促进。在这里，我们解决的问题有多少激活的转化相关的转录因子[激活蛋白-1（AP-1），三元复合物因子（TCF），或核因子κ-B（NF-κ-B）]是需要转化反应和多少肿瘤启动子产生重大的转化风险。建立了携带具有AP-1应答元件、血清应答元件（SRE）或NF-κ-B应答元件的报道构建体的稳定转染子。我们研究了肿瘤启动子浓度、关键信号事件和转录因子激活之间的关系。浓度> 0.2 nM TPA或0.12 ng/mL（0.02 nM）EGF产生转化反应以及细胞外信号调节蛋白激酶（ERK）、SRE或AP-1活化的显著增加。用> 0.4 U/mL（2.35 pM）TNF-α处理以剂量依赖性方式增加NF-κ-B活性和转化反应。然而，由于细胞毒性反应，转化反应在> 33 U/mL TNF-α时降低。这些发现表明，导致ERK、TCF和AP-1蛋白活化的信号通路构成了决定TPA或EGF促进肿瘤风险的主要因素。在预测TNF-α诱导的转化反应时，除NF-κ-B活化外，还应考虑细胞毒性。
The promotion-sensitive mouse epidermal JB6 cells (clone 41) have been used to identify the tumor-promoting activity of various compounds. Because treatment by tumor promoters [12-O-tetradecanoylphorbol-13-acetate (TPA), epidermal growth factor (EGF), or tumor necrosis factor alpha (TNF-alpha)] transforms clone 41 cells to anchorage-independent and tumorigenic phenotypes, they are considered to be undergoing late-stage tumor promotion. Here we address the question of how much activation of transformation-relevant transcription factors [activator protein-1 (AP-1), ternary complex factors (TCFs), or nuclear factor kappa-B (NF-kappa-B)] is required for transformation response and how much tumor promoter produces significant risk of transformation. Stable transfectants harboring a reporter construct with an AP-1 response element, serum-response element (SRE), or NF-kappa-B response element were established. We examined the relationship between concentration of tumor promoters, key signaling events, and activation of the transcription factors. A concentration of > 0.2 nM TPA or 0.12 ng/mL (0.02 nM) EGF produced a significant increase in transformation response as well as in extracellular signal-regulated protein kinase (ERK), SRE, or AP-1 activation. Treatment with > 0.4 U/mL (2.35 pM) TNF-alpha increased NF-kappa-B activity and transformation response in a dose-dependent manner. However, transformation response decreased at > 33 U/mL TNF-alpha due to a cytotoxic response. These findings suggest that the signaling pathway leading to the activation of ERK, TCF, and AP-1 proteins constitutes a major factor determining the risk of tumor promotion by TPA or EGF. Cell toxicity in addition to NF-kappa-B activation should be considered in predicting TNF-alpha-induced transformation response.
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影响因子：
10.4
作者：
KITCHIN, KT;BROWN, JL;SETZER, RW
通讯作者：
SETZER, RW
影响因子：
4.7
作者：
LU, YP;CHANG, RL;CONNEY, AH
通讯作者：
CONNEY, AH
影响因子：
82.9
作者：
Moore, RJ;Owens, DM;Balkwill, F
通讯作者：
Balkwill, F
影响因子：
11.4
作者：
Janknecht, R;Hunter, T
通讯作者：
Hunter, T
DOI：
10.1073/pnas.91.2.609
发表时间：
1994-01-18
影响因子：
11.1
作者：
DONG, ZG;BIRRER, MJ;COLBURN, NH
通讯作者：
COLBURN, NH