Interferon-γ Induces X-linked Inhibitor of Apoptosis-associated Factor-1 and Noxa Expression and Potentiates Human Vascular Smooth Muscle Cell Apoptosis by STAT3 Activation

Bai, Yalai; Ahmad, Usman; Wang, Yinong; Li, Jie H.; Choy, Jonathan C.; Kim, Richard W.; Kirkiles-Smith, Nancy C.; Maher, Stephen E.; Karras, James G.; Bennett, C. Frank; Bothwell, Alfred L.M.; Pober, Jordan S.; Tellides, George

doi:10.1074/jbc.m706021200

Cited by 34 publications

(30 citation statements)

References 52 publications

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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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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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“…Given the significantly reduced GVHD in both BMT settings, it appears that the increased expansion of Tregs as well as the attenuated Th1 differentiation trumped the reduced AICD. Furthermore, it is possible that IFN-γ-mediated suppression of Tregs is critically dependent on the presence of Stat1, whereas IFN-γ-dependent AICD of donor T cells may utilize Stat1-independent signaling pathways (57). In addition, the role of IFN-γ in regulating GVHD is influenced by conditioning intensity (13) and may further depend on the presence and intensity of allostimulation from host hematopoietic cells.…”

Section: Discussionmentioning

confidence: 99%

Absence of Stat1 in donor CD4+ T cells promotes the expansion of Tregs and reduces graft-versus-host disease in mice

Ma¹,

Lu²,

Ziegler³

et al. 2011

J. Clin. Invest.

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“…However, we have observed that the mutant virus produces a large-plaque phenotype and have measured a higher induction of cell death in E95D-infected cells. Although generally considered to be antiapoptotic (3), STAT3 has been demonstrated to participate in the induction of apoptosis in specific situations and cell types (5,19). Considering that STAT1 targeting in the absence of STAT3 targeting would create an unusual situation for mumps virus, it seems reasonable to predict that more dramatic consequences would result from the E95D mutant virus in vivo if an appropriate model system were available.…”

Section: Discussionmentioning

confidence: 99%

A Point Mutation, E95D, in the Mumps Virus V Protein Disengages STAT3 Targeting from STAT1 Targeting

Puri

Lemon

Duprex

et al. 2009

J Virol

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Mumps virus, like other paramyxoviruses in the Rubulavirus genus, encodes a V protein that can assemble a ubiquitin ligase complex from cellular components, leading to the destruction of cellular signal transducer and activator of transcription (STAT) proteins. While many V proteins target the interferon-activated STAT1 or STAT2 protein, mumps virus V protein is unique in its ability to also target STAT3 for ubiquitin modification and proteasome-mediated degradation. Here we report that a single amino acid substitution in the mumps virus V protein, E95D, results in defective STAT3 targeting while maintaining the ability to target STAT1. Results indicate that the E95D mutation disrupts the ability of the V protein to associate with STAT3. A recombinant mumps virus carrying the E95D mutation in its P and V proteins replicates normally in cultured cells but fails to induce targeting of STAT3. Infection with the recombinant virus results in the differential regulation of a number of cellular genes compared to wild-type mumps virus and increases cell death in infected cells, producing a large-plaque phenotype.

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Interferon-γ Induces X-linked Inhibitor of Apoptosis-associated Factor-1 and Noxa Expression and Potentiates Human Vascular Smooth Muscle Cell Apoptosis by STAT3 Activation

Abstract: Interferon (IFN)-

Cited by 34 publications

References 52 publications

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

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

Absence of Stat1 in donor CD4+ T cells promotes the expansion of Tregs and reduces graft-versus-host disease in mice

A Point Mutation, E95D, in the Mumps Virus V Protein Disengages STAT3 Targeting from STAT1 Targeting

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