Yang Y, Pan X, Lei W, Wang J, Song J
Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Oncogene. 2006 Nov 23;25(55):7235-44. doi: 10.1038/sj.onc.1209712. Epub 2006 Jun 26.
Apoptosis and epithelial-to-mesenchymal transition (EMT) have been implicated in a variety of biological processes, such as embryonic development, fibrosis and tumor progression. Transforming growth factor-beta (TGF-beta) can induce simultaneously both EMT and apoptotic response of epithelial cells. However, the underlying mechanism of these biological events remains not well understood. In the present study, we show that TGF-beta1 induces apoptosis and EMT in AML-12 cells in a cell cycle-related manner, in which apoptosis and EMT took place at G2/M and G1/S phases, respectively. TGF-beta1-induced apoptosis was correlated with different extent of caspase activation at different cell cycle phases. Interestingly, increased phosphorylation of protein kinase D (PKD) can be observed in G1/S phase in response to TGF-beta1, and inhibition of PKD by inhibitor or by small interference RNA blocked EMT but not apoptosis. Our data suggest a previously unrecognized role of cell cycle state in the regulation of TGF-beta-induced EMT and apoptosis, and demonstrate that PKD is involved in the TGF-beta1-induced EMT.
细胞凋亡和上皮-间质转化（EMT）与多种生物学过程相关，如胚胎发育、纤维化和肿瘤进展。转化生长因子-β（TGF-β）可同时诱导上皮细胞发生EMT和凋亡反应。然而，这些生物学事件的潜在机制仍未完全明确。在本研究中，我们发现TGF-β1以细胞周期相关的方式诱导AML-12细胞发生凋亡和EMT，其中凋亡和EMT分别发生在G2/M期和G1/S期。TGF-β1诱导的凋亡与不同细胞周期阶段半胱天冬酶激活的不同程度相关。有趣的是，在G1/S期可观察到蛋白激酶D（PKD）的磷酸化增加，这是对TGF-β1的反应，并且用抑制剂或小干扰RNA抑制PKD可阻断EMT，但不影响凋亡。我们的数据表明细胞周期状态在调节TGF-β诱导的EMT和凋亡中具有先前未被认识到的作用，并证明PKD参与TGF-β1诱导的EMT。
