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Targets of transcriptional regulation by transforming growth factor-beta: expression profile analysis using
S Akiyoshi1, M Ishii, N Nemoto
1Department 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.
Abstract:
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.
Insights
Transforming growth factor-betas (TGF-betas) inhibit cell proliferation and can suppress tumors. This study identified novel genes regulated by TGF-beta, revealing its complex role in cancer through both gene activation and repression.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Signaling
Background:
- Transforming growth factor-betas (TGF-betas) are crucial regulators of cell proliferation, and their signaling pathway is frequently disrupted in cancer.
- Understanding the transcriptional targets of TGF-beta is essential for elucidating its role in tumorigenesis.
Purpose of the Study:
- To identify novel transcriptional targets of TGF-beta using gene expression profiling.
- To investigate the direct and indirect transcriptional regulation by TGF-beta.
Main Methods:
- Gene expression profiling of HaCaT keratinocytes treated with TGF-beta, with and without cycloheximide (CHX).
- Oligonucleotide array hybridization to analyze the expression of approximately 5600 human genes.
- Validation of known TGF-beta responsive genes.
Main Results:
- TGF-beta up-regulated known genes like PAI-1, junB, p21 cdk inhibitor, Smad7, betaIG-H3, and involucrin.
- BetaIG-H3 induction by TGF-beta was abolished by CHX, indicating indirect regulation.
- More genes were down-regulated than up-regulated by TGF-beta, including epithelial-specific Ets, potentially contributing to tumor suppression.
Conclusions:
- TGF-beta regulates a broad spectrum of genes, including those involved in cell cycle control and epithelial characteristics.
- TGF-beta may exert tumor suppressive effects by repressing genes associated with tumorigenesis, such as epithelial-specific Ets.
- TGF-beta influences tumorigenesis through both positive and negative transcriptional regulation.