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Downregulation of telomerase reverse transcriptase mRNA expression by wild type p53 in human tumor cells

Oncogene volume 19, pages 5123–5133 (2000)Cite this article

Abstract

The p53 tumor suppressor protein inhibits the formation of tumors through induction of cell cycle arrest and/or apoptosis. In the present study we demonstrated that p53 is also a powerful inhibitor of human telomerase reverse transcriptase (hTERT), a key component for telomerase. Activation of either exogenous temperature-sensitive (ts) p53 in BL41 Burkitt lymphoma cells or endogenous wild type (wt) p53 at a physiological level in MCF-7 breast carcinoma cells triggered a rapid downregulation of hTERT mRNA expression, independently of the induction of the p53 target gene p21. Co-transfection of an hTERT promoter construct with wt p53 but not mutant p53 in HeLa cells inhibited the hTERT promoter activity. Furthermore, the activation of the hTERT promoter in Drosophila Schneider SL2 cells was completely dependent on the ectopic expression of Sp1 and was abrogated by wt p53. Finally, wt p53 inhibited Sp1 binding to the hTERT proximal promoter by forming a p53-Sp1 complex. Since activation of telomerase, widely observed in human tumor cell lines and primary tumors, is a critical step in tumorigenesis, wt p53-triggered inhibition of hTERT/telomerase expression may reflect yet another mechanism of p53-mediated tumor suppression. Our findings provide new insights into both the biological function of p53 and the regulation of hTERT/telomerase expression.

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Acknowledgements

We thank Dr S Bacchetti (McMaster University, Canada) for providing hTERT promoter vectors and for critical reading of the manuscript, Dr R Tjian (University of California, Berkeley, CA, USA) for providing pPacU and pPacSp1 expression vectors, Drs WL Gerald and KA Kolquist (Memorial Sloan-Kettering Cancer Center, New York, USA) for hTERT probe. This work was supported by the Swedish Cancer Society, the Cancer Society in Stockholm, Karolinska Institute Funds, Dagmar Ferbs Memorial Fund, Stockholm County Council and the King Gustaf V Jubilee Fund. P Prisa is a research fellow of the Swedish Medical Research Council.

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Authors and Affiliations

  1. Department of Medicine, Division of Hematology, Radiumhemmet, Karolinska Hospital, SE-171 76, Stockholm, Sweden

    Dawei Xu, Astrid Gruber, Magnus Björkholm & Zhiguo Chen

  2. Department of Oncology, Radiumhemmet, Karolinska Hospital, SE-171 76, Stockholm, Sweden

    Pavel Pisa

  3. Microbiology & Tumor Biology Center, Karolinska Institute, SE-171 77, Stockholm, Sweden

    Qian Wang, Galina Selivanova & Klas G Wiman

  4. Department of Biochemistry, Stockholm University, SE-104 05, Stockholm, Sweden

    Ahmed Zaid

  5. Clinical Pharmacology, Faculty of Health Science, Linköping University, SE-581 85, Linköping, Sweden

    Curt Peterson

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  1. Dawei Xu
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Xu, D., Wang, Q., Gruber, A. et al. Downregulation of telomerase reverse transcriptase mRNA expression by wild type p53 in human tumor cells. Oncogene 19, 5123–5133 (2000). https://doi.org/10.1038/sj.onc.1203890

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