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Apoptosis or growth arrest: modulation of the cellular response to p53 by proliferative signals

Oncogene volume 22, pages 555–571 (2003)Cite this article

Abstract

Activation of the tumor suppressor p53 after genotoxic insults may result in two different responses: growth arrest or apoptosis. In this study, we analysed how mitogenic stimulation of primary mouse lymphocytes influences p53 signaling upon γ-irradiation. We found that G0 lymphocytes rapidly went into p53-dependent apoptosis, whereas stimulated lymphocytes went into a p53-dependent, p21-mediated growth arrest. The switch in p53 response upon stimulation did neither result from a switch in transcriptional activation of major p53 target genes, nor from the high level of p21 expressed in stimulated, irradiated cells. Growth stimulation, however, led to the upregulation of the antiapoptotic factors Bcl-xL and Bfl-1. In resting cells, p53 induced apoptosis after γ-irradiation was accompanied by a breakdown of the mitochondrial membrane potential (Ψm) that was counteracted by growth stimulation. We propose that growth stimulation intercepted p53 proapoptotic signaling at the level of mitochondrial integrity, most likely by upregulating the antiapoptotic factors Bcl-xL and Bfl-1. Upregulation of Bcl-xL and of Bfl-1 upon growth stimulation was mediated by the PKC-dependent activation of NF-κB. Consequently, blocking PKC activity restored apoptosis in stimulated, irradiated splenocytes. The inherent coupling of growth stimulation with antiapoptotic signaling in primary lymphocytes might provide hints as to how precancerous lymphocytes bypass the need for mutational inactivation of p53. Thus, our findings might explain the relatively low frequency of p53 mutations in lymphomas in comparison to other tumor entities.

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Abbreviations

ConA:

Concanavalin A

EMSA:

electrophoretic mobility shift assay

FITC:

fluorescein isothiocyanate

NF-κB:

nuclear factor κB

PE:

phycoerythrin

PKC:

protein kinase C

PMA:

phorbol 12-myristate 13-acetate

PVDF:

polyvinylidene difluoride

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Acknowledgements

We thank Phil Leder (Harvard Medical School, Boston, MA, USA) for kindly providing FvB/n p21−/− mice. This work was supported by Deutsche Krebshilfe (Mildred Scheel Stiftung), grant 10-1457-De 5 (‘Apoptosedefizienz und ihre Modulation bei malignen Erkrankungen’) and the Fonds des Chemisohen Industrie. The Heinrich-Pette-Institute is financially supported by Freie und Hansestadt Hamburg and Bundesministerium für Gesundheit. Many data are part of the PhD thesis of Stefan Heinrichs.

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  1. Heinrich-Pette-Institut für Experimentelle Virologie und Immunologie an der Universität Hamburg, Martinistrasse 52, Hamburg, D-20251, Germany

    Stefan Heinrichs & Wolfgang Deppert

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Correspondence to Wolfgang Deppert.

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Heinrichs, S., Deppert, W. Apoptosis or growth arrest: modulation of the cellular response to p53 by proliferative signals. Oncogene 22, 555–571 (2003). https://doi.org/10.1038/sj.onc.1206138

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