Akiyoshi S, Ishii M, Nemoto N, Kawabata M, Aburatani H, Miyazono K
Department of Biochemistry, The Cancer Institute of Japanese Foundation for Cancer Research (JFCR), and Research for the Future Program, the Japan Society for the Promotion of Science, Toshima-ku, Tokyo 170-8455, Japan.
Jpn J Cancer Res. 2001 Mar;92(3):257-68. doi: 10.1111/j.1349-7006.2001.tb01090.x.
Transforming growth factor-betas (TGF-betas) are potent inhibitors of cell proliferation, and disruption of components of the TGF-beta signaling pathway leads to tumorigenesis. Mutations of transmembrane receptors and Smads mediating intracellular signaling have been reported in various cancers. To identify transcriptional targets of TGF-beta, we conducted an expression profile analysis. HaCaT cells derived from human keratinocytes and highly sensitive to TGF-beta were treated with TGF-beta in the absence or presence of cycloheximide (CHX). mRNAs extracted from the HaCaT cells were used for hybridization of oligonucleotide arrays representing approximately 5600 human genes. TGF-beta increased the expression of PAI-1, junB, p21 cdk inhibitor, Smad7, betaIG-H3, and involucrin that have been reported to be up-regulated by TGF-beta, validating the usefulness of this approach. The induction of betaIG-H3 by TGF-beta was completely abolished by CHX, suggesting that the transcription of betaIG-H3 is not directly regulated by TGF-beta. Unexpectedly, we identified more genes down-regulated by TGF-beta than up-regulated ones. TGF-beta repressed the expression of epithelial specific Ets that may be involved in breast and lung tumorigenesis, which could contribute to tumor suppression by TGF-beta. Among a panel of cell cycle regulators, TGF-beta induced the expression of p21 cdk inhibitor; however, the induction of other cdk inhibitors was not significant in the present study. Taken together, the results suggest that TGF-beta may suppress tumorigenesis through positive and negative regulation of transcription.
转化生长因子-β（TGF-β）是细胞增殖的强效抑制剂，TGF-β信号通路成分的破坏会导致肿瘤发生。在各种癌症中均已报道了介导细胞内信号传导的跨膜受体和Smad的突变。为了鉴定TGF-β的转录靶标，我们进行了表达谱分析。用人角质形成细胞来源且对TGF-β高度敏感的HaCaT细胞，在不存在或存在环己酰亚胺（CHX）的情况下用TGF-β处理。从HaCaT细胞中提取的mRNA用于与代表约5600个人类基因的寡核苷酸阵列杂交。TGF-β增加了PAI-1、junB、p21 cdk抑制剂、Smad7、βIG-H3和内披蛋白的表达，这些基因已被报道受TGF-β上调，证实了该方法的有效性。TGF-β对βIG-H3的诱导被CHX完全消除，表明βIG-H3的转录不受TGF-β直接调控。出乎意料的是，我们鉴定出受TGF-β下调的基因比上调的基因更多。TGF-β抑制了可能参与乳腺癌和肺癌发生的上皮特异性Ets的表达，这可能有助于TGF-β的肿瘤抑制作用。在一组细胞周期调节因子中，TGF-β诱导了p21 cdk抑制剂的表达；然而，在本研究中其他cdk抑制剂的诱导并不显著。综上所述，结果表明TGF-β可能通过转录的正负调控来抑制肿瘤发生。
