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Interferons α and γ induce p53-dependent and p53-independent apoptosis, respectively

Oncogene volume 24, pages 605–615 (2005)Cite this article

Abstract

Type I interferon (IFN) enhances the transcription of the tumor suppressor gene p53. To elucidate the molecular mechanism mediating IFN-induced apoptosis, we analysed programmed cell death in response to type I (IFNα) or type II (IFNγ) treatment in relation to p53 status. In two cell lines (MCF-7, SKNSH), IFNα, but not IFNγ, enhanced apoptosis in a p53-dependent manner. Furthermore, only IFNα upregulated p53 as well as p53 target genes (Noxa, Mdm2 and CD95). The apoptotic response to IFNα decreased in the presence of ZB4, an anti-CD95 antibody, suggesting that CD95 is involved in this process. When p53 was inactivated by the E6 viral protein or the expression of a p53 mutant, IFNα-induced apoptosis and p53 target genes upregulation were abrogated. Altogether these results demonstrate that p53 plays a pivotal role in the IFNα-induced apoptotic response. IFNα-induced PML was unable to recruit p53 into nuclear bodies and its downregulation by siRNA did not alter CD95 expression. In contrast, IFNγ-induced apoptosis is p53-independent. CD95 and IFN-regulatory factor 1 (IRF1) are directly upregulated by this cytokine. Apoptotic response to IFNγ is decreased in the presence of ZB4 and strongly diminished by IRF1 siRNA, implicating both CD95 and IRF1 in IFNγ-induced apoptotic response. Taken together, these results show that in two different cell lines, IFNα and IFNγ, induce p53-dependent -independent apoptosis, respectively.

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Abbreviations

FADD:

Fas-associated death domain

IFN:

interferon

PML:

promyelocytic leukemia-related gene/protein

APL:

acute promyelocyic leukemia

NBs:

nuclear bodies

PKR:

RNA-dependent protein kinase

HIPK2:

homeodomain-interacting protein kinase 2

IRF1:

IFN-regulatory factor 1

STAT:

signal tranducer and activator of transcription

JAK:

Janus kinase

ISRE:

IFN-stimulated response element

GAS:

gamma-activating sequence

SUMO:

small ubiquitin modifier

siRNA:

small interfering RNA

ISG:

IFN-stimulated gene

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Acknowledgements

We would like to thank Evelyne May for providing materials and critical reading of the manuscript, Jean-Christophe Bourdon for the gift of SKNSH DD p53 cells, Pier Giuseppe Pelicci for the gift of PMLIV expressing vector and Marie Vincent for technical assistance. This work was supported by CNRS and grants from Ligue Nationale Contre le Cancer. LE is funded by fellowships from ANRS and MN from NRB.

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Author notes

  1. Chiara Porta and Reda Hadj-Slimane: These authors contributed equally to this work

Authors and Affiliations

  1. UPR CNRS 9045, Institut André Lwoff, 7 rue Guy Moquet, 94801, Villejuif, France

    Chiara Porta, Reda Hadj-Slimane, Mohamed Nejmeddine, Mathieu Pampin, Michael G Tovey, Lucile Espert & Mounira K Chelbi-Alix

  2. UMR217 CEA-CNRS, Fontenay-aux-Roses Cedex, France

    Sandra Alvarez

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  1. Chiara Porta
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Correspondence to Mounira K Chelbi-Alix.

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Porta, C., Hadj-Slimane, R., Nejmeddine, M. et al. Interferons α and γ induce p53-dependent and p53-independent apoptosis, respectively. Oncogene 24, 605–615 (2005). https://doi.org/10.1038/sj.onc.1208204

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