Smad4-independent regulation of p21/WAF1 by transforming growth factor-β
Smad4-independent regulation of p21/WAF1 by transforming growth factor-β
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DOI：
10.1038/sj.onc.1207222
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发表时间：
2004-02-05
期刊：
影响因子：
8
通讯作者：
Omata, M
中科院分区：
文献类型：
--
作者：
Ijichi, H;Otsuka, M;Omata, M
转化生长因子-β（TGF-β）-Smad信号通路抑制人上皮细胞的生长并在肿瘤抑制中起作用。Smad 4基因在50%的胰腺癌中突变或缺失。在这项研究中，Smad 4-null胰腺癌细胞系BxPC-3用Smad 4表达载体或空载体转染，并在存在或不存在TGF-β的情况下孵育。使用cDNA微阵列对细胞进行分析，该cDNA微阵列包括2280个命名基因以筛选由TGF-β以Smad 4依赖或非依赖方式调节的靶基因。微阵列和随后的定量RT-PCR分析表明，由TGF-β驱动的Smad 4非依赖性和依赖性信号通路分别仅上调2280个基因中的一个，这表明TGF-β下游的Smad 4非依赖性信号转导可能与Smad 4依赖性信号转导一样广泛。在这项研究中，我们证明了细胞周期蛋白依赖性激酶抑制剂p21/WAF 1，这已被认为是TGF-β的Smad依赖性生长抑制信号的主要效应，是在Smad 4独立的方式上调。上调通过Smad 2/3依赖性转录激活p21/WAF 1启动子区发生。这些结果表明，一种新的基因调控机制，即一种新的信号介质以外的Smad 4。
The transforming growth factor-beta (TGF-beta)-Smad signaling pathway inhibits the growth of human epithelial cells and plays a role in tumor suppression. The Smad4 gene is mutated or deleted in 50% of pancreatic cancers. In this study, the Smad4-null pancreatic cancer cell line BxPC-3 was transfected with either the Smad4 expression vector or the empty vector and incubated in the presence or absence of TGF-beta. The cells were analysed using a cDNA microarray, which included 2280 named genes to screen for target genes regulated by TGF-beta in either a Smad4-dependent or -independent manner. The microarray and subsequent quantitative RT-PCR analysis demonstrated that the Smad4-independent and -dependent signaling pathways driven by TGF-beta upregulated only one of the 2280 genes, respectively, suggesting that Smad4-independent signaling downstream of TGF-beta might be as widespread as Smad4-dependent signaling. In this study, we demonstrated that the cyclin-dependent kinase inhibitor p21/WAF1, which has been considered the major effector of the Smad-dependent growth inhibitory signal of TGF-beta, is upregulated in a Smad4-independent manner. The upregulation occurs through Smad2/3-dependent transcriptional activation of the p21/WAF1 promoter region. These results suggest a novel mechanism of gene regulation, that is, a novel signal mediator other than Smad4.