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  • Original Paper
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Tumor suppressor p53 inhibits transcriptional activation of invasion gene thromboxane synthase mediated by the proto-oncogenic factor ets-1

Abstract

Cancer formation and progression is a complex process determined by several mechanisms that promote cell growth, invasiveness, neo-angiogenesis, and render neoplastic cells resistant to apoptosis. The tumor suppressor p53 and the proto-oncogenic factor ets-1 are important regulators of such mechanisms. While it is well established that p53 and ets-1 influence various aspects of cell behavior by regulating the transcription of specific genes, little is known about the functional relationship between these transcription factors. We found that the gene encoding thromboxane synthase (TXSA), which we recently identified as a factor promoting invasion and resistance to apoptosis in gliomas, is a novel target gene for both p53 and ets-1. We demonstrate that p53 and ets-1 coregulate TXSA in an antagonistic and inter-related manner, with ets-1 being a potent transcriptional activator and p53 inhibiting ets-1-dependent transcription. Negative interference with ets-1 transcription requires functional p53 and is lost in mutant p53 proteins. We show that ets-1 and p53 associate physically in vitro and in vivo and that their interaction, rather than a direct binding of p53 to the TXSA promoter, is required for transcriptional repression of TXSA by wild-type p53. An important implication of our findings is that the loss of p53-mediated negative control over ets-1-dependent transcription may lead to the acquisition of an invasive phenotype in tumor cells.

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Acknowledgements

We thank Sker Freist for his assistance in the preparation of the illustrations. This work was supported by Deutsche Forschungsgemeinschaft (Gi 218/2-2 and Gi-218/2-4, granted to A.G.), Deutsche Krebshilfe (10-1417-De4, granted to W.D.), and by Fonds der Chemischen Industrie. Dr Yoshizato was supported by a Fellowship from the Bauer Foundation of the University of Hamburg. The Heinrich-Pette-Institut is financially supported by Freie und Hansestadt Hamburg and Bundesministerium für Gesundheit.

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Correspondence to Alf Giese.

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Kim, E., Günther, W., Yoshizato, K. et al. Tumor suppressor p53 inhibits transcriptional activation of invasion gene thromboxane synthase mediated by the proto-oncogenic factor ets-1. Oncogene 22, 7716–7727 (2003). https://doi.org/10.1038/sj.onc.1207155

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