Article
Functional interaction between tumor suppressor p53 and proto-oncogene Ets-1 determines the invasive potential of glial tumors
Die Interaktion von Tumorsuppressor p53 und Proto-Onkogen Ets-1 bestimmt das invasive Potential glialer Tumore
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Published: | April 23, 2004 |
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Outline
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Objective
The proto-oncogenic factor Ets-1 is directly associated with progression and invasion and is frequently overexpressed in gliomas but not in normal glial cells. While the importance of Ets-1 in glioma invasion has already been established, the mechanisms leading to deregulated expression of Ets-1 remain poorly understood. We have recently discovered that the transcriptional activity of Ets-1 is under the control of tumor suppressor p53, which associates physically with the Ets-1 protein and abrogates Ets-1 dependent expression of anti-apoptotic and invasion genes.
Methods
Steady-state levels of the Ets-1 protein were examined in glioma cells lines by western blot. p53´s transcriptional activity was induced in lines expressing wild type p53 by γ-radiation. Expression pattern of known p53 target genes MDM2 and P21 were used to determine p53´s transcriptional activity.
Results
The negative control of Ets-1 activities by p53 extends beyond physical interaction between the two proteins. Not only the Ets-1 activity, but also expression of the Ets-1 protein, is under a negative control by p53. Inhibition of Ets-1 expression requires transcriptionally active p53 protein and is no longer affected by p53 mutants. Treatment of glioma cells with γ-radiation in regimens similar to those used in clinical practice induces ets-1 depending on the functional status of the p53 protein.
Conclusions
Our findings identify Ets-1 as a novel target gene of p53. Based on our findings we propose that aberrant interaction between p53 and Ets-1 determines the high invasive potential and resistance to apoptosis in gliomas. Furthermore, we propose that in cells with impaired function of tumor suppressor p53, γ-radiation leads to induction of Ets-1 and subsequent induction of anti-apoptotic and invasion-associated genes.