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Gadd45β is a pro-survival factor associated with stress-resistant tumors

Oncogene volume 27, pages 1429–1438 (2008)Cite this article

Abstract

Tumors that acquire resistance against death stimuli constitute a severe problem in the context of cancer therapy. To determine genetic alterations that favor the development of stress-resistant tumors in vivo, we took advantage of polyclonal tumors generated after retroviral infection of newborn Eλ-MYC mice, in which the retroviral integration acts as a mutagen to enhance tumor progression. Tumor cells were cultivated ex vivo and exposed to γ-irradiation prior to their transplantation into syngenic recipients, thereby providing a strong selective pressure for pro-survival mutations. Secondary tumors developing from stress-resistant tumor stem cells were analysed for retroviral integration sites to reveal candidate genes whose dysregulation confer survival. In addition to the gene encoding the antiapoptotic Bcl-xL protein, we identified the gadd45b locus to be a novel common integration site in these tumors, leading to enhanced expression. In accord with a thus far undocumented role of Gadd45β in tumorigenesis, we showed that NIH3T3 cells overexpressing Gadd45β form tumors in NOD/SCID mice. Interestingly and differently to other known ‘classical’ antiapoptotic factors, high Gadd45β levels did not protect against MYC-, UV- or γ-irradiation-induced apoptosis, but conferred a strong and specific survival advantage to serum withdrawal.

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Abbreviations

4OHT:

4-hydroxytamoxifen

CIS:

common integration site

eGFP:

enhanced green fluorescent protein

FACS:

fluorescence-activated cell sorting

Mo-MuLV:

Moloney-murine leukemia virus

PI:

propidium iodide

RT:

reverse transcriptase

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Acknowledgements

We thank Karen Blyth and Ewan Cameron for conditional MYC overexpressing cell lines, Arne Düsedau for providing FACS sorter support and other members of the Stocking laboratory for helpful discussions. This work was part of the doctoral thesis of A Engelmann, Department of Biology, University of Hamburg, Hamburg, Germany and was supported by a grant of the Deutsche Krebshilfe. The Heinrich-Pette-Institut is supported by the Freie und Hansestadt Hamburg and the German Ministry of Health and Social Safety.

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Authors and Affiliations

  1. Heinrich-Pette-Institut, Hamburg, Germany

    A Engelmann, D Speidel, W Deppert & C Stocking

  2. GSF-Forschungszentrum für Umwelt und Gesundheit, Institut für Klinische Molekularbiologie und Tumorgenetik, Munich, Germany

    G W Bornkamm

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  1. A Engelmann
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  2. D Speidel
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Correspondence to C Stocking.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Engelmann, A., Speidel, D., Bornkamm, G. et al. Gadd45β is a pro-survival factor associated with stress-resistant tumors. Oncogene 27, 1429–1438 (2008). https://doi.org/10.1038/sj.onc.1210772

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