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Regulation of telomerase activity by the p53 family member p73

Oncogene volume 25, pages 813–826 (2006)Cite this article

Abstract

The terminal ends of eukaryotic chromosomes, termed telomeres, progressively shorten during each round of cell division eventually leading cells into senescence. Tumor cells typically overcome this barrier to unlimited proliferation by activation of the human telomerase reverse transcriptase (hTERT) gene. In contrast, in most human somatic cells hTERT expression is tightly repressed by multiple tumor suppressors. Here, we studied the regulation of hTERT by the p53 family member p73. We show that forced expression of p73 or activation of endogenous p73 by E2F1 results in the downregulation of telomerase activity. Vice versa, siRNA-mediated knockdown of p73 induces hTERT expression. Responsiveness to p73 is conferred by Sp1 binding sites within the hTERT core promoter. In tumor cells, p73 isoforms lacking the transactivation domain (ΔNp73) are frequently overexpressed and believed to function as oncogenes. We show that ΔNp73 antagonizes the repressive effect of the proapoptotic p53 family members on hTERT expression and, in addition, induces hTERT expression in telomerase-negative cells by interfering with E2F-RB-mediated repression of the hTERT core promoter. These data provide evidence that the p73 gene functions as an important regulator of telomerase activity with implications for embryonic development, cellular differentiation and tumorigenesis.

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Acknowledgements

We thank Didier Trono, Satoru Kyo, Martin Eilers, Bert Vogelstein, Jonathan Horowitz, Gerry Melino, Chikashi Ishioka, Scott Lowe, Guntram Suske, Kristian Helin and Eric Knudsen for providing plasmids; Karen Vousden for the gift of H1299 tet-on cells; and Nadja Karl for excellent technical assistance. This work was supported by grants of the Deutsche Forschungsgemeinschaft (DFG FZ82) and the Deutsche Krebshilfe – Dr Mildred Scheel Stiftung (DKH 10-2075-St2).

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  1. Molecular Tumor Biology Group, Rudolf-Virchow-Center (DFG Research Center for Experimental Biomedicine), University of Würzburg, Würzburg, Germany

    M Beitzinger, C Oswald, R Beinoraviciute-Kellner & T Stiewe

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  1. M Beitzinger
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Correspondence to T Stiewe.

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Beitzinger, M., Oswald, C., Beinoraviciute-Kellner, R. et al. Regulation of telomerase activity by the p53 family member p73. Oncogene 25, 813–826 (2006). https://doi.org/10.1038/sj.onc.1209125

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