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Originally published In Press as doi:10.1074/jbc.M309260200 on February 9, 2004
J. Biol. Chem., Vol. 279, Issue 19, 20167-20177, May 7, 2004
Identification of Transcription Factor Binding Sites Upstream of Human Genes Regulated by the Phosphatidylinositol 3-Kinase and MEK/ERK Signaling Pathways*
John W. Tullai  ,
Michael E. Schaffer¶,
Steven Mullenbrock,
Simon Kasif¶||, and
Geoffrey M. Cooper¶**
From the
Department of Biology, ¶Bioinformatics Program, and the ||Department of Biomedical Engineering, Boston University, Boston, Massachusetts 02215
We have taken an integrated approach in which expression profiling has been combined with the use of small molecule inhibitors and computational analysis of transcription factor binding sites to characterize regulatory sequences of genes that are targets of specific signaling pathways in growth factor-stimulated human cells. T98G cells were stimulated with platelet-derived growth factor (PDGF) and analyzed by DNA microarrays, which identified 74 immediate-early gene transcripts. Cells were then treated with inhibitors to identify subsets of genes that are targets of the phosphatidylinositol 3-kinase (PI3K) and MEK/ERK signaling pathways. Four groups of PDGF-induced genes were defined: independent of PI3K and MEK/ERK signaling, dependent on PI3K signaling, dependent on MEK/ERK signaling, and dependent on both pathways. The upstream regions of all genes in the four groups were scanned using TRANSFAC for putative cis-elements as compared with a background set of non-induced genes. Binding sites for 18 computationally predicted transcription factors were over-represented in the four groups of co-expressed genes compared with the background sequences (p < 0.01). Many of the cis-elements identified were conserved in orthologous mouse genes, and many of the predicted elements and their cognate transcription factors were consistent with previous experimental data. In addition, chromatin immunoprecipitation assays experimentally verified nine predicted SRF binding sites in T98G cells, including a previously unknown SRF site upstream of DUSP5. These results indicate that groups of human genes regulated by discrete intracellular signaling pathways share common cis-regulatory elements.
Received for publication, August 20, 2003
, and in revised form, February 2, 2004.
The microarray gene expression data from this study has been submitted to GEO (Gene Expression Omnibus) under accession number GSE1128.
* This work was supported by Grants R01 CA18689 and P20 GM66401 and fellowship F32 GM067392 (to J. W. T.) from the National Institutes of Health, and D90-9870710 and KDI-9980088 from the National Science Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
The on-line version of this article (available at http://www.jbc.org) contains Supplementary Data.
 These authors contributed equally to this study.
** To whom correspondence should be addressed: Boston University, Dept. of Biology, 5 Cummington St., Boston, MA 02215. Tel.: 617-353-8735; Fax: 617-353-8484; E-mail: gmcooper{at}bu.edu.
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Copyright © 2004 by the American Society for Biochemistry and Molecular Biology.
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