TGF beta regulation of mitogen-activated protein kinases in human breast cancer cells
TGF beta regulation of mitogen-activated protein kinases in human breast cancer cells
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DOI：
10.1016/s0304-3835(97)00211-5
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发表时间：
1997-07-15
期刊：
影响因子：
9.7
通讯作者：
Mulder, KM
中科院分区：
文献类型：
--
作者：
Frey, RS;Mulder, KM
我们在此证明了转化生长因子-β-2（TGF β（2））在高度TGF β敏感的乳腺癌细胞（BCC）系Hs 578 T中有效激活细胞外信号调节激酶2（ERK 2）的能力。在加入TGF β 2后5分钟内，ERK 2亚型被激活3倍。然而，TGF β 2在部分TGF β反应的BCC细胞系MDA-MB-231中仅轻微激活ERK 2（1.5倍）。在两种细胞系中，TGF β 2激活ERK 2的差异幅度与TGF β抑制DNA合成的IC 50值的差异一致; MDA-MB-231细胞中的IC 50值是Hs 578 T细胞中的32倍。此外，我们的数据表明，TGF β（2）激活应激活化蛋白激酶/Jun N-末端激酶（SAPK/JNK）类型的丝裂原活化蛋白激酶（MAPK）;最大诱导水平是基础值的2.5倍，并在TGF β（2）处理后30分钟达到。瞬时共转染含有三个AP-1位点和纤溶酶原激活物抑制剂-1（派-1）启动子的荧光素酶报告基因构建体（3 TP-Lux），与指导显性阴性突变体ERK 2（TAYF）蛋白表达的构建体结合，确实净阻断了TGF β诱导AP-1或派-1活性的能力。相反，TAYF ERK 2能够阻断EGF和胰岛素诱导的3 TP-Lux报告基因活性。这些结果表明，在这些BCC中，TGF β对ERK 2的激活与TGF β抑制DNA合成的能力比刺激对TGF β产生和控制细胞外基质重要的启动子区域的能力更紧密地联系在一起。此外，这是第一次证明TGF β可以激活TGF β敏感的人BCC中的SAPK/JNK类型的MAPK。(C)1997 Elsevier Science爱尔兰有限公司
We demonstrate herein the ability of transforming growth factor-beta-2 (TGF beta(2)) to potently activate extracellular signal-regulated kinase 2 (ERK2) in the highly TGF beta-sensitive breast cancer cell (BCC) line Hs578T. The ERK2 isoform was activated by 3-fold within 5 min of TGF beta(2) addition to Hs578T cells. However, TGF beta(2) only slightly activated ERK2 (1.5-fold) in the partially TGF beta-responsive BCC line MDA-MB-231. The magnitude of the difference in activation of ERK2 by TGF beta(2) in the two cell lines paralleled the difference in the IC50 values for TGF beta inhibition of DNA synthesis; the IC50 value in the MDA-MB-231 cells was 32-fold greater than that in the Hs578T cells. Further, our data demonstrate that TGF beta(2) activated the stress-activated protein kinase/Jun N-terminal kinase (SAPK/JNK) type of mitogen-activated protein kinases (MAPKs); maximal induction levels were 2.5-fold above basal values and were attained at 30 min after TGF beta(2) treatment. Transient co-transfection of a luciferase reporter construct (3TP-Lux) containing three AP-1 sites and the plasminogen activator inhibitor-1 (PAI-1) promoter, in conjunction with a construct that directs expression of a dominant-negative mutant ERK2 (TAYF) protein, did net block the ability of TGF beta to induce AP-1 or PAI-1 activity. In contrast, TAYF ERK2 was able to block EGF and insulin-induced 3TP-Lux-reporter activity. These results indicate that in these BCCs, the activation of ERK2 by TGF beta is more tightly linked to the ability of TGF beta to inhibit DNA synthesis than to the ability to stimulate promoter regions important for TGF beta production and control of the extracellular matrix. In addition, this is the first demonstration that TGF beta can activate the SAPK/JNK type of MAPK in TGF beta-sensitive human BCCs. (C) 1997 Elsevier Science Ireland Ltd.