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

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 (IFNy) 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.