Frey R S, Mulder K M
Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey 17033, USA.
Cancer Res. 1997 Feb 15;57(4):628-33.
Although transforming growth factor beta (TGF-beta) is known to be a potent growth inhibitor of breast cancer cells (BCCs), the signaling mechanisms mediating TGF-beta responses have not been defined. We have demonstrated previously that TGF-beta can activate Ras and extracellular signal-regulated kinase (ERK) 1 in untransformed epithelial cells (K. M. Mulder and S. L. Morris, J. Biol. Chem., 267: 5029-5031, 1992; M. T. Hartsough and K. M. Mulder, J. Biol. Chem., 270: 7117-7124, 1995). We have also shown that TGF-beta signaling is altered in epithelial cells when Ras activation is blocked (Hartsough et at., J. Biol. Chem., 271: 22368-22375). Here we demonstrate the ability of the TGF-beta3 isoform to activate the signaling component ERK2 in TGF-beta-sensitive BCCs but not in TGF-beta-resistant cells. The ERK2 isoform was activated by 6-fold within 10 min of TGF-beta3 addition to the TGF-beta-sensitive BCC line Hs578T. Moreover, the IC50 for inhibition of DNA synthesis by TGF-beta3 in this cell line correlated with the EC50 for TGF-beta3 activation of ERK2. In contrast, TGF-beta3 had little effect on either DNA synthesis or ERK2 activation in ZR-75 BCCs lacking the type-II TGF-beta receptors (R(II)), or in ZR-75 BCCs stably transfected with R(II) yet still TGF-beta resistant. In addition, our data demonstrate that TGF-beta3 affected a sustained activation of the stress-activated protein kinase/Jun N-terminal kinase (SAPK/JNK) type of mitogen-activated protein kinase (MAPK); maximal induction levels were 2.5-fold above basal values and were attained at 30 min after TGF-beta3 treatment. In contrast, TGF-beta3 did not increase SAPK/JNK activity in the TGF-beta-resistant ZR-75 R(II) BCCs. Our data provide the first evidence that TGF-beta activation of ERK2 and SAPK/JNK is associated with negative growth control of BCCs. This is also the first demonstration that TGF-beta can activate the SAPK/JNK type of MAPK and that the TGF-beta3 isoform can regulate MAPK activity.
虽然已知转化生长因子β（TGF-β）是乳腺癌细胞（BCC）的一种强效生长抑制剂，但介导TGF-β反应的信号传导机制尚未明确。我们之前已经证明，TGF-β可以在未转化的上皮细胞中激活Ras和细胞外信号调节激酶（ERK）1（K.M.穆德和S.L.莫里斯，《生物化学杂志》，267:5029 - 5031，1992；M.T.哈索和K.M.穆德，《生物化学杂志》，270:7117 - 7124，1995）。我们还表明，当Ras激活被阻断时，上皮细胞中的TGF-β信号传导会发生改变（哈索等人，《生物化学杂志》，271:22368 - 22375）。在此，我们证明了TGF-β3亚型能够在对TGF-β敏感的BCC中激活信号成分ERK2，但在对TGF-β耐药的细胞中则不能。在向对TGF-β敏感的BCC系Hs578T添加TGF-β3后10分钟内，ERK2亚型被激活了6倍。此外，该细胞系中TGF-β3抑制DNA合成的IC50与TGF-β3激活ERK2的EC50相关。相比之下，TGF-β3对缺乏II型TGF-β受体（R(II)）的ZR - 75 BCC或稳定转染了R(II)但仍对TGF-β耐药的ZR - 75 BCC的DNA合成或ERK2激活几乎没有影响。此外，我们的数据表明，TGF-β3影响了应激激活蛋白激酶/ Jun N端激酶（SAPK/JNK）类型的丝裂原激活蛋白激酶（MAPK）的持续激活；最大诱导水平比基础值高2.5倍，在TGF-β3处理后30分钟达到。相比之下，TGF-β3在对TGF-β耐药的ZR - 75 R(II) BCC中并未增加SAPK/JNK活性。我们的数据提供了首个证据，表明TGF-β对ERK2和SAPK/JNK的激活与BCC的负生长控制相关。这也是首次证明TGF-β可以激活SAPK/JNK类型的MAPK，以及TGF-β3亚型可以调节MAPK活性。
