A Functional SNP in the MDM2 Promoter Mediates E2F1 Affinity to Modulate Cyclin D1 Expression in Tumor Cell Proliferation
| Autor: | Jiu-Hong Li, Zhen-Hai Yang, Chun-Lin Zhou, Chun-Di He, Hong Zhu |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
endocrine system
Cancer Research Skin Neoplasms Epidemiology Cyclin D Cyclin A Cyclin B medicine.disease_cause Cyclin D1 Cell Line Tumor medicine Humans E2F1 Promoter Regions Genetic Cell Proliferation Regulation of gene expression biology Public Health Environmental and Occupational Health Proto-Oncogene Proteins c-mdm2 Fibroblasts Gene Expression Regulation Neoplastic Oncology biology.protein Cancer research biological phenomena cell phenomena and immunity Carcinogenesis E2F1 Transcription Factor Cyclin A2 |
| Zdroj: | Asian Pacific Journal of Cancer Prevention. 15:3817-3823 |
| ISSN: | 1513-7368 |
| DOI: | 10.7314/apjcp.2014.15.8.3817 |
| Popis: | Background: The MDM2 oncogene, a negative regulator of p53, has a functional polymorphism in the promoter region (SNP309) that is associated with multiple kinds of cancers including non-melanoma skin cancer. SNP309 has been shown to associate with accelerated tumor formation by increasing the affinity of the transcriptional activator Sp1. It remains unknown whether there are other factors involved in the regulation of MDM2 transcription through a trans-regulatory mechanism. Methods: In this study, SNP309 was verified to be associated with overexpression of MDM2 in tumor cells. Bioinformatics predicts that the T to G substitution at SNP309 generates a stronger E2F1 binding site, which was confirmed by ChIP and luciferase assays. Results: E2F1 knockdown downregulates the expression of MDM2, which confirms that E2F1 is a functional upstream regulator. Furthermore, tumor cells with the GG genotype exhibited a higher proliferation rate than TT, correlating with cyclin D1 expression. E2F1 depletion significantly inhibits the proliferation capacity and downregulates cyclin D1 expression, especially in GG genotype skin fibroblasts. Notably, E2F1 siRNA effects could be rescued by cyclin D1 overexpression. Conclusion: Taken together, a novel modulator E2F1 was identified as regulating MDM2 expression dependent on SNP309 and further mediates cyclin D1 expression and tumor cell proliferation. E2F1 might act as an important factor for SNP309 serving as a rate-limiting event in carcinogenesis. |
| Databáze: | OpenAIRE |
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