<p> PEA3 is a member of the expanding Ets family of transcription factors. In the adult mouse, pea3 mRNA is expressed at highest levels in the brain, epididymis and at lower levels in the mammary gland, testes, ovary and uterus. PEA3 is overexpressed in 93% of all HER2/Neu positive human breast tumors and in 77% of mouse multiple intestinal (Min) tumors. Many of these tumors have disruptions in the Ras/MAPK and Wnt signaling pathways. Analysis of the influence of these pathways on pea3 promoter activity revealed that effectors of both pathways increased transcription from this promoter. Deletion mutations of the pea3 promoter linked to a luciferase reporter gene were used to localize the DNA sequences that are responsible for the effect of the Ras/MAPK pathway on its expression. A Ras-responsive element (RRE), composed of an ETS and an AP-1 binding site, was identified between sequences -247 and -227 and its importance was confirmed through mutational analysis. </p> <p> CYCLIN Dl is a potent oncogene involved in different types of tumors. The CYCLIN D1 gene is amplified in 20% of human mammary carcinomas, and its mRNA is overexpressed in 50% of human breast cancers. The CYCLIN Dl (CDJ) promoter was shown to be responsive to PEA3 transactivation and to dominant-negative PEA3 inhibition in co-transfection experiments in Cos-1 cells. Of the 4 Ets-binding sites (EBS) in the CDJ promoter, one site was shown to be important for the activity of the promoter and for its capacity to respond to PEA3 transactivation. It was also determined that PEA3, ~-catenin, Lef-1 and c-Jun cooperated synergistically to activate the CDJ promoter. PEA3 was absolutely required for the manifestation of this synergy among these transcription factors. These findings collectively illustrate the key role of PEA3 as an effector of multiple oncogenic signaling pathways. </p> / Thesis / Master of Science (MSc)
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/22673 |
| Date | 05 1900 |
| Creators | Messier, Cynthia |
| Contributors | Hassell, J.A., Biochemistry |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
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