Targets of Transcriptional Regulation by Transforming Growth Factor‐β: Expression Profile Analysis Using Oligonucleotide Arrays

Transforming growth factor‐βs (TGF‐βs) are potent inhibitors of cell proliferation, and disruption of components of the TGF‐β signaling pathway leads to tumorigenesis. Mutations of transmem‐brane receptors and Smads mediating intracellular signaling have been reported in various cancers. To identify transcriptional targets of TGF‐β, we conducted an expression profile analysis. HaCaT cells derived from human keratinocytes and highly sensitive to TGF‐β were treated with TGF‐β 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‐β increased the expression of PAI‐1, junB, p21 cdk inhibitor, Smad7, βIG‐H3, and involucrin that have been reported to be up‐regulated by TGF‐β, validating the usefulness of this approach. The induction of βIG‐H3 by TGF‐β was completely abolished by CHX, suggesting that the transcription of βIG‐H3 is not directly regulated by TGF‐β. Unexpectedly, we identified more genes down‐regulated by TGF‐β than up‐regulated ones. TGF‐β repressed the expression of epithelial specific Ets that may be involved in breast and lung tumorigenesis, which could contribute to tumor suppression by TGF‐β. Among a panel of cell cycle regulators, TGF‐β 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‐β may suppress tumorigenesis through positive and negative regulation of transcription.