Targets of transcriptional regulation by transforming growth factor-β:: Expression profile analysis using oligonucleotide arrays
Targets of transcriptional regulation by transforming growth factor-β:: Expression profile analysis using oligonucleotide arrays
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DOI：
10.1111/j.1349-7006.2001.tb01090.x
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发表时间：
2001-03-01
期刊：
影响因子：
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通讯作者：
Miyazono, K
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文献类型：
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作者：
Akiyoshi, S;Ishii, M;Miyazono, K
转化生长因子-β（TGF-β）是细胞增殖的有效抑制剂，并且TGF-β信号传导途径的组分的破坏导致肿瘤发生。已经报道了在各种癌症中介导细胞内信号传导的跨膜受体和Smads的突变。为了鉴定TGF-β的转录靶点，我们进行了表达谱分析。在存在或不存在放线菌酮（CHX）的情况下，用TGF-β处理源自人角质形成细胞并且对TGF-β高度敏感的HaCaT细胞，将从HaCaT细胞提取的mRNA用于代表约5600个人基因的寡核苷酸阵列的杂交。TGF-β增加了派-1、junB、p21 cdk抑制剂、Smad 7、β IG-H3和外皮蛋白的表达，这些蛋白已被报道被TGF-β上调，验证了这种方法的有用性。TGF-β对β IG-H3的诱导作用被CHX完全消除，表明β IG-H3的转录不受TGF-β的直接调节。出乎意料的是，我们鉴定出TGF-β下调的基因多于上调的基因。TGF-β抑制了上皮特异性Ets的表达，这些Ets可能参与了乳腺和肺肿瘤的发生，这可能有助于TGF-β抑制肿瘤的发生。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抑制剂的诱导作用不显著。总之，结果表明，TGF-β可能通过转录的正向和负向调节来抑制肿瘤发生。
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, beta IG-H3, and involucrin that have been reported to be up-regulated by TGF-beta, validating the usefulness of this approach. The induction of beta IG-H3 by TGF-beta was completely abolished by CHX, suggesting that the transcription of beta IG-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.