Inhibitory effect of Bcl-2 on p53-mediated transactivation following genotoxic stress
| Autor: | Kontny U, Maite Iglesias, Craig D. Woodworth, Yu K, Albert J. Fornace, Qimin Zhan, M C Hollander, I Alamo |
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| Rok vydání: | 1999 |
| Předmět: |
Transcriptional Activation
Cancer Research Cell cycle checkpoint Tumor suppressor gene Cell growth Gadd45 DNA repair Apoptosis Genotoxic Stress Biology Cell cycle Methyl Methanesulfonate Transactivation Gene Expression Regulation Proto-Oncogene Proteins c-bcl-2 Tumor Cells Cultured Genetics Cancer research Humans Tumor Suppressor Protein p53 Molecular Biology DNA Damage Mutagens |
| Zdroj: | Oncogene. 18:297-304 |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/sj.onc.1202310 |
| Popis: | In the cellular response to genotoxic stress, cell cycle checkpoint and apoptosis are considered to be two of the major biological events in maintaining genomic stability. The tumor suppressor p53 has been shown to play critical roles in these stress-induced cellular responses at least in part through the activation of its down-stream genes, such as p21CIP1/WAF1, GADD45 and BAX. In addition, p53 has been found to down-regulate the expression of BCL-2, which is able to block apoptosis induced by both p53-dependent and independent signaling events. In this report, we have found that increased expression of Bcl-2 protein in the human Burkitt's lymphoma WMN cell line suppressed apoptosis induced by different DNA-damaging agents. The induction of p53-regulated genes including GADD45, p21CIP1/WAF1 and BAX by genotoxic stress was substantially reduced in cells expressing high levels of Bcl-2 protein. Furthermore, Bcl-2 protein was shown to specifically suppress the p53-mediated transactivation of p21CIP1/WAF1 and PG13-CAT, which is a typical p53-binding-site reporter construct. Similarly, the inhibitory effect of Bcl-2 protein was seen in a GADD45 promoter reporter construct after treatment with methylmethane sulfonate or UV-radiation. These results indicate that in addition to its apoptosis-suppressing activity, Bcl-2 protein is able to inhibit transactivation of p53-regulated genes, which function in multiple important cellular responses to genotoxic stress, including the control of cell cycle checkpoints, cell growth suppression and DNA repair. |
| Databáze: | OpenAIRE |
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