Article
Transcriptional activity of invasion-promoting factor ets-1 is regulated differently by wild-type and mutant p53 in glial tumors
Differentielle Regulation der transkriptionellen Aktivität des invasionsfördernden Faktors ets-1 durch wild-typ und mutiertes p53 in glialen Tumoren
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Published: | May 4, 2005 |
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Outline
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Objective
Proto-oncogene ets-1 is an important cellular factor contributing to the acquisition of the increased invasive potential and resistance to apoptosis in malignant gliomas. The major mechanism underlying oncogenic activities of ets-1 involves transcriptional activation of invasion/ anti-apoptotic genes by ets-1 binding to DNA. Ets-1 activity is under negative control of tumour suppressor p53, which is found frequently mutated in gliomas. In contrast to wtp53, which inhibits ets-1 activities, the impact of mutant p53 protein on ets-1 activity remains unclear. Main objective of this study was to examine ets-1 activities in glioma cells expressing mutant p53.
Methods
Ets-1 transcriptional activity was assessed in a panel of glioma cell lines with the known status of p53. GBM derived clones with inducible expression of wild-type or mutant p53 proteins were used additionally. Expression of ets-1 and of ets-1 regulated genes was analyzed by immunoprecipitation, Western Blotting and RT-PCR analyses in untreated cells or after exposure to y-irradiation.
Results
Overexpression of ets-1 leads to an increased cell motility and expression of invasion associated genes. Using GBM derived cell lines with regulatable expression of p53 we show that wild-type and mutant p53 proteins influence ets-1 transcriptional activity differently. In contrast to wild type p53, which inhibits ets-1 activity, some mutant p53 proteins have stimulatory effects and co-operate with ets-1 in activating invasion-associated genes. Furthermore, we find that y-irradiation can potently induce ets-1 expression in gliomas with mutant p53 but not in cells expressing wild-type p53 protein. In addition, the results indicate that the mdm-2 protein may be an important mediator of p53 effects on ets-1 activity.
Conclusions
Our results indicate that invasion-promoting factor ets-1 is under the tight control of tumor-suppressor p53. Connections between p53 pathway and ets-1 transcriptional activity appear to occur at different levels and may involve various mechanisms. Our findings reveal that p53 is directly involved in the control of glioma invasion and that mutant p53 contributes to the increase of the invasive potential in gliomas by enhancing ets-1 transcriptional activity. An important implication from our findings is thatvarious cellular responses may be induced by y-irradiation, which is a commonly used modality in glioma treatment depending on the functional status of both p53 and ets-1.