Deregulation of Internal Ribosome Entry Site-Mediated p53 Translation in Cancer Cells with Defective p53 Response to DNA Damage
| Autor: | Margot P. Cleary, Benjamin R E Harris, W. Keith Miskimins, Da-Qing Yang, Marie Jo Halaby |
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| Rok vydání: | 2015 |
| Předmět: |
Untranslated region
DNA damage Breast Neoplasms Internal Ribosome Entry Sites Biology medicine.disease_cause DEAD-box RNA Helicases Cell Line Tumor medicine Protein biosynthesis Humans Breast Nuclear Factor 90 Proteins Molecular Biology Messenger RNA fungi Translation (biology) Articles Cell Biology Neoplasm Proteins Gene Expression Regulation Neoplastic Internal ribosome entry site Protein Biosynthesis Proteolysis Cancer cell MCF-7 Cells Cancer research Female Tumor Suppressor Protein p53 5' Untranslated Regions Carcinogenesis DNA Damage Protein Binding |
| Zdroj: | Molecular and Cellular Biology. 35:4006-4017 |
| ISSN: | 1098-5549 |
| DOI: | 10.1128/mcb.00365-15 |
| Popis: | Synthesis of the p53 tumor suppressor and its subsequent activation following DNA damage are critical for its protection against tumorigenesis. We previously discovered an internal ribosome entry site (IRES) at the 5' untranslated region of the p53 mRNA. However, the connection between IRES-mediated p53 translation and p53's tumor suppressive function is unknown. In this study, we identified two p53 IRES trans-acting factors, translational control protein 80 (TCP80), and RNA helicase A (RHA), which positively regulate p53 IRES activity. Overexpression of TCP80 and RHA also leads to increased expression and synthesis of p53. Furthermore, we discovered two breast cancer cell lines that retain wild-type p53 but exhibit defective p53 induction and synthesis following DNA damage. The levels of TCP80 and RHA are extremely low in both cell lines, and expression of both proteins is required to significantly increase the p53 IRES activity in these cells. Moreover, we found cancer cells transfected with a shRNA against TCP80 not only exhibit decreased expression of TCP80 and RHA but also display defective p53 induction and diminished ability to induce senescence following DNA damage. Therefore, our findings reveal a novel mechanism of p53 inactivation that links deregulation of IRES-mediated p53 translation with tumorigenesis. |
| Databáze: | OpenAIRE |
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