Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Egr1 regulates the coordinated expression of numerous EGF receptor target genes as identified by ChIP-on-chip

ABSTRACT: Previous studies have revealed that UV-stimulation of a variety of cells leads to activation of the EGF receptor, induction of Egr1, growth inhibition and apoptosis. On the other hand both Egr1 and EGF receptor activation are implicated in promoting the progression of prostate cancer. We treated M12 tumorigenic prostate epithelial cells which express little Egr1 with UV irradiation which rapidly activated the EGF receptor and elevated Egr1. Treatment with specific EGFR and ERKI/II inhibitors (PD153035 and UO126, respectively) confirmed that the upregulation of Egr1 was downstream of EGFR and ERKI/II Map kinase pathway. ChIP on chip experiments using Egr1 antibody identified 288 significantly bound promoters upon UV stimulation. Of these target genes, 40% had consensus Egr1 site in their promoters, considerably greater than that expected by chance (p < 0.005). The array binding results were validated by PCR analysis of 25 genes using DNA from conventional IP experiment. Affymetrix gene expression analysis of UV treated and control cells confirmed that a significant number of these bound promoters showed gene expression changes. Addition of siRNA to Egr1 confirmed that the gene expression changes were dependent upon Egr1 expression. Addition of EGF led to similar expression changes for nine tested genes. Proliferation and apoptosis assays confirmed that M12 cells undergo growth arrest and apoptosis following UV irradiation. Moreover, addition of EGF also promoted significant growth inhibition. These results indicate the M12 cells undergo a EGF receptor dependent apoptosis response upon UV-stimulation and that Egr1 mediates the regulation of numerous genes downstream of the EGF receptor that are associated with this response. Keywords: UV treatment analysis duplicated experiment for Affymetrix gene expression analysis and Chip-on-Chip analysis.

ORGANISM(S): Homo sapiens

SUBMITTER: Yipeng Wang

PROVIDER: E-GEOD-10585 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Egr1 regulates the coordinated expression of numerous EGF receptor target genes as identified by ChIP-on-chip.

Arora Shilpi S Wang Yipeng Y Jia Zhenyu Z Vardar-Sengul Saynur S Munawar Ayla A Doctor Kutbuddin S KS Birrer Michael M McClelland Michael M Adamson Eileen E Mercola Dan D

Genome biology 20081125 11

<h4>Background</h4>UV irradiation activates the epidermal growth factor receptor, induces Egr1 expression and promotes apoptosis in a variety of cell types. We examined the hypothesis that Egr1 regulates genes that mediate this process by use of a chip-on-chip protocol in human tumorigenic prostate M12 cells.<h4>Results</h4>UV irradiation led to significant binding of 288 gene promoters by Egr1. A major functional subgroup consisted of apoptosis related genes. The largest subgroup of 24 genes be ...[more]

PMID: 19032775

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Project description:SF-1, a transcription factor belonging to the nuclear receptor superfamily, has a pivotal role for adrenogonadal development in humans and mice. A constant feature of childhood adrenocortical tumors (ACT) is SF-1 amplification and overexpression. Using an inducible cellular system, here we show that SF-1 overexpression increases human adrenocortical cell proliferation through opposing effects on cell cycle and apoptosis. SF-1 overexpression also selectively modulates steroidogenesis, reducing cortisol and aldosterone secretion. We identified a novel pro-apoptotic factor for adrenocortical cells, NOV/CCN3, whose levels are significantly reduced by SF-1 overexpression in human adrenocortical cells and are also reduced in primary adrenal tumors. Moreover, Sf-1 overexpression triggers adrenocortical hyperplasia and tumor formation in mice. These tumors express gonadal markers and activated Stat3. Our studies reveal the critical role of SF-1 gene dosage for adrenocortical tumorigenesis and constitute a rationale for the development of drugs targeting SF-1 transcriptional activity for ACT therapy. Keywords: comparative gene expression Gene expression profiles were analyzed by two-color microarrays in transgenic mice from line #56 heterozygous or homozygous for the transgene, male or female and of different ages. Profiles from each transgenic mouse were directly compared to a sex- and age-matched wild-type littermate. For each experimental point, two technical replicates (dye-swaps) were examined. Array # Age Sex Transgene copy # Cy3 Cy5 16682 10 days M 1 WT transgenic 16479 10 days M 1 transgenic WT 16683 10 days M 1 WT transgenic 16625 10 days M 1 transgenic WT 16685 10 days F 1 WT transgenic 16680 10 days F 1 transgenic WT 16516 4 months M 2 WT transgenic 16452 4 months M 2 transgenic WT 16517 4 months M 2 WT transgenic 16453 4 months M 2 transgenic WT 16518 4 months F 2 WT transgenic 16475 4 months F 2 transgenic WT

Dataset Information

Egr1 regulates the coordinated expression of numerous EGF receptor target genes as identified by ChIP-on-chip

Publications

Egr1 regulates the coordinated expression of numerous EGF receptor target genes as identified by ChIP-on-chip.

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