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  • Original Paper
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An alternatively spliced survivin variant is positively regulated by p53 and sensitizes leukemia cells to chemotherapy

Oncogene volume 23, pages 7545–7551 (2004)Cite this article

Abstract

Survivin is a unique member of the inhibitor of apoptosis protein family, and its expression is regulated by p53. Recent identification of several functionally divergent survivin variants augments the complexity of survivin action as well as its regulation. Here we report that survivin-2B (retaining a part of intron 2 as a cryptic exon) is positively regulated by p53, and its overexpression plays a role in sensitizing leukemia cells to chemotherapeutic drug doxorubicin. Doxorubicin treatment activated p53, downregulated survivin and survivin-ΔEx3 but upregulated survivin-2B in EU-3, an acute lymphocytic leukemia (ALL) cell line with wild-type (wt)-p53 phenotype. In contrast, doxorubicin treatment failed to induce these alterations in EU-6 cells, a mutant-p53 ALL cell line. To specify the role of wt-p53 in regulating survivin and its variants, a temperature-sensitive p53 mutant plasmid p53-143 was transfected into EU-4, a p53-null ALL cell line, to establish a subline EU-4/p53-143. When EU-4/p53-143 cell culture was shifted from 37.5°C to the wt-p53-permissive temperature (32.5°C), the expression of survivin and survivin-ΔEx3 was decreased whereas survivin-2B expression was increased, confirming the distinct regulatory effect of p53 on survivin and its variants. To clarify the role of survivin-2B in the process of apoptosis, survivin-2B cDNA was cloned into pcDNA3HA vector and transfected into EU-4 cells. Enforced expression of survivin-2B in EU-4 cells inhibited cell growth and sensitized these cells to doxorubicin-induced apoptosis. These results suggest that survivin-2B variant is a proapoptotic factor and its expression is upregulated by p53.

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Acknowledgements

This work was supported by grants from the NCI-NIH (R01 CA82323), CURE Childhood Cancer Inc.

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Authors and Affiliations

  1. Department of Pediatrics, Emory University School of Medicine, Atlanta, 30322, GA, USA

    Ningxi Zhu, Lubing Gu, Harry W Findley & Muxiang Zhou

  2. Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA

    Fengzhi Li

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Correspondence to Muxiang Zhou.

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Zhu, N., Gu, L., Findley, H. et al. An alternatively spliced survivin variant is positively regulated by p53 and sensitizes leukemia cells to chemotherapy. Oncogene 23, 7545–7551 (2004). https://doi.org/10.1038/sj.onc.1208038

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