Targets of transcriptional regulation by transforming growth factor-beta: Expression profile analysis using oligonucleotide arrays

Transforming growth factor-betas (TGF-betas) are potent inhibitors of cell proliferation, and disruption of components of the TGF-beta signaling pathw ay leads to tumorigenesis. Mutations of transmembrane receptors and Smads m ediating intracellular signaling have been reported in various cancers, To identify transcriptional targets of TGF-beta, we conducted an expression pr ofile analysis. HaCaT cells derived from human keratinocytes and highly sen sitive 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 hy bridization 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-regula ted 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, Unex pectedly; we identified more genes down-regulated by TGF-beta than up-regul ated ones. TGF-beta repressed the expression of epithelial specific Ets tha t may be involved in breast and lung tumorigenesis, which could contribute to tumor suppression by TGF-beta, Among a panel of cell cycle regulators, T GF-beta induced the expression of p21 cdk inhibitor; however, the induction of other cdk inhibitors was not significant in the present study. Taken to gether, the results suggest that TGF-beta may suppress tumorigenesis throug h positive and negative regulation of transcription.