The puzzling regulation of the interferon signaling system by the p53 tumor suppressor protein
Abstract The p53 tumor suppressor exhibits antiviral activity. The viral replication is also inhibited by interferons (IFNs), cytokines that regulate immune genes via STAT transcription factors. The best studied interferons belong to the type I (e.g., IFNα1) and type II (IFNγ) groups. IFNα1 and IFNγ...
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2025-06-01
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| Online Access: | https://doi.org/10.1007/s00018-025-05763-0 |
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| author | Agnieszka Będzińska Barbara Łasut-Szyszka Małgorzata Krześniak Agnieszka Gdowicz-Kłosok Marek Rusin |
| author_facet | Agnieszka Będzińska Barbara Łasut-Szyszka Małgorzata Krześniak Agnieszka Gdowicz-Kłosok Marek Rusin |
| author_sort | Agnieszka Będzińska |
| collection | DOAJ |
| description | Abstract The p53 tumor suppressor exhibits antiviral activity. The viral replication is also inhibited by interferons (IFNs), cytokines that regulate immune genes via STAT transcription factors. The best studied interferons belong to the type I (e.g., IFNα1) and type II (IFNγ) groups. IFNα1 and IFNγ induce the phosphorylation of STAT1 at Tyr701. Previously, we reported that p53 activates SOCS1, a negative regulator of STAT1 phosphorylation. Based on this, we hypothesized that p53, by activating SOCS1, reduces the phosphorylation of STAT1 and attenuates the activation of genes stimulated either by IFNα1 or IFNγ. To test this hypothesis, we exposed p53-proficient and p53-deficient cells to p53 activators along with either IFNα1 or IFNγ. We then assessed STAT1 phosphorylation and the expression of interferon-regulated genes. Strong p53 activation reduced the STAT1 phosphorylation at Tyr701; however, it did not decrease the expression of most of the tested interferon-stimulated genes. On the contrary, IFNγ synergized with p53 to enhance CASP1, IFIT1 and IFIT3 expression. We conclude that the interactions between p53 and interferon-activated pathways are more complicated than initially expected, and their cooperation deserves further investigation. Moreover, we found that SOCS1 can be either up- or down-regulated by p53 depending on cell type and stress conditions. |
| format | Article |
| id | doaj-art-373855579ebc4cfb93cabdac1ed1acac |
| institution | DOAJ |
| issn | 1420-9071 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Springer |
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| series | Cellular and Molecular Life Sciences |
| spelling | doaj-art-373855579ebc4cfb93cabdac1ed1acac2025-08-20T03:21:02ZengSpringerCellular and Molecular Life Sciences1420-90712025-06-0182111910.1007/s00018-025-05763-0The puzzling regulation of the interferon signaling system by the p53 tumor suppressor proteinAgnieszka Będzińska0Barbara Łasut-Szyszka1Małgorzata Krześniak2Agnieszka Gdowicz-Kłosok3Marek Rusin4Center for Translational Research and Molecular Biology of Cancer, Maria Skłodowska-Curie National Research Institute of Oncology, Gliwice BranchCenter for Translational Research and Molecular Biology of Cancer, Maria Skłodowska-Curie National Research Institute of Oncology, Gliwice BranchCenter for Translational Research and Molecular Biology of Cancer, Maria Skłodowska-Curie National Research Institute of Oncology, Gliwice BranchCenter for Translational Research and Molecular Biology of Cancer, Maria Skłodowska-Curie National Research Institute of Oncology, Gliwice BranchCenter for Translational Research and Molecular Biology of Cancer, Maria Skłodowska-Curie National Research Institute of Oncology, Gliwice BranchAbstract The p53 tumor suppressor exhibits antiviral activity. The viral replication is also inhibited by interferons (IFNs), cytokines that regulate immune genes via STAT transcription factors. The best studied interferons belong to the type I (e.g., IFNα1) and type II (IFNγ) groups. IFNα1 and IFNγ induce the phosphorylation of STAT1 at Tyr701. Previously, we reported that p53 activates SOCS1, a negative regulator of STAT1 phosphorylation. Based on this, we hypothesized that p53, by activating SOCS1, reduces the phosphorylation of STAT1 and attenuates the activation of genes stimulated either by IFNα1 or IFNγ. To test this hypothesis, we exposed p53-proficient and p53-deficient cells to p53 activators along with either IFNα1 or IFNγ. We then assessed STAT1 phosphorylation and the expression of interferon-regulated genes. Strong p53 activation reduced the STAT1 phosphorylation at Tyr701; however, it did not decrease the expression of most of the tested interferon-stimulated genes. On the contrary, IFNγ synergized with p53 to enhance CASP1, IFIT1 and IFIT3 expression. We conclude that the interactions between p53 and interferon-activated pathways are more complicated than initially expected, and their cooperation deserves further investigation. Moreover, we found that SOCS1 can be either up- or down-regulated by p53 depending on cell type and stress conditions.https://doi.org/10.1007/s00018-025-05763-0NK-92FAS ligandInnate immunityPyroptosisIFITM3OAS1 |
| spellingShingle | Agnieszka Będzińska Barbara Łasut-Szyszka Małgorzata Krześniak Agnieszka Gdowicz-Kłosok Marek Rusin The puzzling regulation of the interferon signaling system by the p53 tumor suppressor protein Cellular and Molecular Life Sciences NK-92 FAS ligand Innate immunity Pyroptosis IFITM3 OAS1 |
| title | The puzzling regulation of the interferon signaling system by the p53 tumor suppressor protein |
| title_full | The puzzling regulation of the interferon signaling system by the p53 tumor suppressor protein |
| title_fullStr | The puzzling regulation of the interferon signaling system by the p53 tumor suppressor protein |
| title_full_unstemmed | The puzzling regulation of the interferon signaling system by the p53 tumor suppressor protein |
| title_short | The puzzling regulation of the interferon signaling system by the p53 tumor suppressor protein |
| title_sort | puzzling regulation of the interferon signaling system by the p53 tumor suppressor protein |
| topic | NK-92 FAS ligand Innate immunity Pyroptosis IFITM3 OAS1 |
| url | https://doi.org/10.1007/s00018-025-05763-0 |
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