Single-stranded RNA viruses inactivate the transcriptional activity of p53 but induce NOXA-dependent apoptosis via post-translational modifications of IRF-1, IRF-3 and CREB

Lallemand, Christophe; Blanchard, Brigitte; Palmieri, Marta; Lebon, Pierre; May, Evelyne; Tovey, Michaël G.

doi:10.1038/sj.onc.1209795

Cited by 48 publications

(57 citation statements)

References 42 publications

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“…Our data are in agreement with studies by others who described that transcriptional induction of Noxa is involved in virus-mediated apoptosis (29,30). Noxa and Puma were originally identified as target genes regulated by the tumor suppressor p53 (31,32).…”

Section: Discussionsupporting

confidence: 83%

Proapoptotic signaling induced by RIG-I and MDA-5 results in type I interferon–independent apoptosis in human melanoma cells

Besch¹,

Poeck²,

Hohenauer³

et al. 2009

J. Clin. Invest.

303

436

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The retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated antigen 5 (MDA-5) helicases sense viral RNA in infected cells and initiate antiviral responses such as the production of type I IFNs.Here we have shown that RIG-I and MDA-5 also initiate a proapoptotic signaling pathway that is independent of type I IFNs. In human melanoma cells, this signaling pathway required the mitochondrial adapter Cardif (also known as IPS-1) and induced the proapoptotic BH3-only proteins Puma and Noxa. RIG-I-and MDA-5-initiated apoptosis required Noxa but was independent of the tumor suppressor p53. Triggering this pathway led to efficient activation of mitochondrial apoptosis, requiring caspase-9 and Apaf-1. Surprisingly, this proapoptotic signaling pathway was also active in nonmalignant cells, but these cells were much less sensitive to apoptosis than melanoma cells. Endogenous Bcl-x L rescued nonmalignant, but not melanoma, cells from RIG-I-and MDA-5-mediated apoptosis. In addition, we confirmed the results of the in vitro studies, demonstrating that RIG-I and MDA-5 ligands both reduced human tumor lung metastasis in immunodeficient NOD/SCID mice. These results identify an IFN-independent antiviral signaling pathway initiated by RIG-I and MDA-5 that activates proapoptotic signaling and, unless blocked by Bcl-x L , results in apoptosis. Due to their immunostimulatory and proapoptotic activity, RIG-I and MDA-5 ligands have therapeutic potential due to their ability to overcome the characteristic resistance of melanoma cells to apoptosis.

show abstract

Section: Discussionsupporting

confidence: 83%

Proapoptotic signaling induced by RIG-I and MDA-5 results in type I interferon–independent apoptosis in human melanoma cells

Besch¹,

Poeck²,

Hohenauer³

et al. 2009

J. Clin. Invest.

303

436

View full text Add to dashboard Cite

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“…28,32,33). Consistent with previous reports showing that IFNs transactivate Noxa in endothelial cells, primary macrophages, and various tumor cells through activation of IRF3 and 7 (20,24,34,35), our data show that IFNs upregulate Noxa expression by increasing the expression levels of IRF1, 3, and 7 in a p53-independent manner and that IRF4 can be substantially reduced by IFN-g possibly acting as a counter partner of IRF1, 3, and 7. It is also worth noting that IRF4, an addiction protein of multiple myeloma cells induced by c-myc (36), may allow tumor cells to survive by repressing Noxa expression.…”

Section: Discussionsupporting

confidence: 81%

Suppression of IRF4 by IRF1, 3, and 7 in Noxa Expression Is a Necessary Event for IFN-γ–Mediated Tumor Elimination

Piya

Moon

Song

et al. 2011

Molecular Cancer Research

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IFN-g plays a critical role in tumor immunosurveillance by affecting either immune cells or tumor cells; however, IFN-mediated effects on tumor elimination are largely unknown. In this study, we showed that IFN regulatory factors (IRF) modulated by IFNs up-and downregulated Noxa expression, a prodeath BH3 protein, in various cancer cells. Inhibition of Noxa expression using short hairpin RNA in tumor cells leads to resistance against lipopolysaccharide (LPS)-induced tumor elimination, in which IFN-g is known as a critical effecter in mice. Chromatin immunoprecipitation analysis in both CT26 cells and SP2/0 cells, sensitive and resistant to LPSinduced tumor elimination, respectively, revealed that the responsiveness of IRF1, 3, 4, and 7 in the Noxa promoter region in response to IFN-g might be crucial in LPS-induced tumor elimination. IRF1, 3, and 7 were upregulated by IFN-g and activated Noxa expression, leading to the death of Noxa wild-type baby mouse kidney (BMK) cells but not of Noxa-deficient BMK cells. In contrast, IRF4 acts as a repressor for Noxa expression and inhibits cell death induced by IRF1, 3, or 7. Therefore, although IFN-g alone are not able to induce cell death in tumor cells in vitro, Noxa induction by IFN-g, which is regulated by the balance between its activators (IRF1, 3, and 7) and its repressor (IRF4), is crucial to increasing the susceptibility of tumor cells to immune cell-mediated cytotoxicity. Mol Cancer Res; 9(10); 1356-65. Ó2011 AACR.

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“…STAT1 has been reported to provoke apoptosis. 55 NOXA, an another important apoptosis-inducible gene, 67 was also highly induced by IKK⑀ in the HCV replicon cells . Whether the antiviral activity of IKK⑀.against HCV is mediated through apoptosis remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

The protein kinase IKKε can inhibit HCV expression independently of IFN and its own expression is downregulated in HCV-infected livers

et al. 2006

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H epatitis C virus (HCV) infection leads to the development of chronic hepatitis in 60% to 90% of infected individuals, cirrhosis in 0.5% to 30% of cases, and hepatocellular carcinoma at a rate of 1% to 3% per year. 1 The current approved treatment for HCV infection is pegylated interferon alpha (IFN-␣) in combination with ribavirin. This leads to clearance of the virus in 50% to 80% of cases, depending on the infecting HCV genotype. In particular, HCV of genotype 1 is the most resistant to IFN treatment. 2 HCV can interfere with the response of cells to IFN, through its viral proteins targeting either the IFN-activated JAK/STAT signaling pathway 3-5 or through other processes, leading to inhibition of action of the IFN-induced antiviral proteins. 6 In addition to this, HCV interferes with IFN induction, and more generally, with the induction of the innate immune response. The innate immune response is triggered in response to a variety of pathogens, such as bacteria and viruses, and is essential for a rapid limitation in the spread or action of these pathogens. IFN induction can take place after interaction of extracellular nucleic acids to members of the Toll-like receptor family 7-10 and after viral intrusion in the cytoplasm through the interaction of viral double-stranded RNAs (dsRNAs) with specific RNA helicases, such as RIG-I 11 or MDA-5. 12 For instance, the From the

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Single-stranded RNA viruses inactivate the transcriptional activity of p53 but induce NOXA-dependent apoptosis via post-translational modifications of IRF-1, IRF-3 and CREB

Cited by 48 publications

References 42 publications

Proapoptotic signaling induced by RIG-I and MDA-5 results in type I interferon–independent apoptosis in human melanoma cells

Proapoptotic signaling induced by RIG-I and MDA-5 results in type I interferon–independent apoptosis in human melanoma cells

Suppression of IRF4 by IRF1, 3, and 7 in Noxa Expression Is a Necessary Event for IFN-γ–Mediated Tumor Elimination

The protein kinase IKKε can inhibit HCV expression independently of IFN and its own expression is downregulated in HCV-infected livers

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