Cyclooxygenase-2-derived prostaglandin E(2) stimulates Id-1 transcription Journal Article
| Authors: | Subbaramaiah, K.; Benezra, R.; Hudis, C.; Dannenberg, A. J. |
| Article Title: | Cyclooxygenase-2-derived prostaglandin E(2) stimulates Id-1 transcription |
| Abstract: | Cyclooxygenase-2 (COX-2) and Id-1 are overexpressed in a variety of human malignancies. Recently, each of these genes was found to play a role in mediating breast cancer metastasis to the lungs, but their potential interdependence was not evaluated. Hence, the main objective of the current study was to determine whether COX-2-derived prostaglandin (PGE2) activated Id-1 transcription, leading in turn to increased invasiveness of mammary epithelial cells. In MDA-MB-231 cells, treatment with PGE2 induced Id-1, an effect that was mimicked by an EP4 agonist. PGE 2 via EP4 activated the epidermal growth factor receptor (EGFR) → ERK1/2 pathway, which led to increased expression of Egr-1. PGE2 stimulated EGFR signaling by inducing the release of amphiregulin, an EGFR ligand. The ability of PGE2 to activate Id-1 transcription was mediated by enhanced binding of Egr-1 to the Id-1 promoter. Silencing of COX-2 or pharmacological inhibition of COX-2 led to reduced PGE2 production, decreased Id-1 expression, and reduced migration of cells through extracellular matrix. A similar decrease in cell migration was found when Id-1 was silenced. The interrelationship between COX-2, PGE 2, Id-1, and cell invasiveness was also compared in nontumorigenic SCp2 and tumorigenic SCg6 mammary epithelial cells. Consistent with the findings in MDA-MB-231 cells, COX-2-derived PGE2 induced Id-1, leading in turn to increased cell invasiveness. Taken together, these results suggest that PGE2 via EP4 activated the EGFR→ ERK1/2 → Egr-1 pathway, leading to increased Id-1 transcription and cell invasion. These findings provide new insights into the relationship between COX-2 and Id-1 and their potential role in metastasis. © 2008 by The American Society for Biochemistry and Molecular Biology, Inc. |
| Keywords: | signal transduction; controlled study; human cell; cytology; gene; gene overexpression; models, biological; epidermal growth factor receptor; protein binding; lung cancer; genetic transcription; receptor, epidermal growth factor; transcription, genetic; pathology; dose-response relationship, drug; cell line, tumor; molecular sequence data; cyclooxygenase 2; prostaglandin e2; transcription; mitogen activated protein kinase 1; mitogen activated protein kinase 3; breast epithelium; base sequence; inhibitor of differentiation protein 1; gene silencing; breast metastasis; cell invasion; migration inhibition; amphiregulin; in cells; cyclooxygenase; dinoprostone; breast cancers; invasiveness; early growth response factor 1; rna, ribosomal, 18s; extracellular matrixes; growth kinetics; cell invasions; egfr signaling; epidermal growth factor receptors; human malignancies; inter-dependences; inter-relationships; mammary epithelial cells; pharmacological inhibitions; cox 2 gene; id 1 gene; early growth response protein 1; receptors, prostaglandin e |
| Journal Title: | Journal of Biological Chemistry |
| Volume: | 283 |
| Issue: | 49 |
| ISSN: | 0021-9258 |
| Publisher: | American Society for Biochemistry and Molecular Biology |
| Date Published: | 2008-12-05 |
| Start Page: | 33955 |
| End Page: | 33968 |
| Language: | English |
| DOI: | 10.1074/jbc.M805490200 |
| PUBMED: | 18842581 |
| PROVIDER: | scopus |
| PMCID: | PMC2662219 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 11" - "Export Date: 17 November 2011" - "CODEN: JBCHA" - "Source: Scopus" |
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