Będzińska Agnieszka, Łasut-Szyszka Barbara, Krześniak Małgorzata, Gdowicz-Kłosok Agnieszka, Rusin Marek
Center for Translational Research and Molecular Biology of Cancer, Maria Skłodowska-Curie National Research Institute of Oncology, Gliwice Branch, ul. Wybrzeże Armii Krajowej 15, 44-101, Gliwice, Poland.
Cell Mol Life Sci. 2025 Jun 13;82(1):233. doi: 10.1007/s00018-025-05763-0.
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.
p53肿瘤抑制蛋白具有抗病毒活性。病毒复制也受到干扰素（IFN）的抑制，干扰素是一类通过信号转导和转录激活因子（STAT）转录因子调节免疫基因的细胞因子。研究得最为透彻的干扰素属于I型（如IFNα1）和II型（IFNγ）。IFNα1和IFNγ可诱导STAT1在Tyr701位点发生磷酸化。此前，我们报道p53可激活SOCS1，而SOCS1是STAT1磷酸化的负调控因子。基于此，我们推测p53通过激活SOCS1，可降低STAT1的磷酸化水平，并减弱由IFNα1或IFNγ刺激的基因的激活。为验证这一假设，我们将p53功能正常和p53缺失的细胞与p53激活剂以及IFNα1或IFNγ一起孵育。然后，我们评估了STAT1的磷酸化水平以及干扰素调节基因的表达。强烈的p53激活可降低Tyr701位点的STAT1磷酸化水平；然而，它并未降低大多数测试的干扰素刺激基因的表达。相反，IFNγ与p53协同作用，增强了CASP1、IFIT1和IFIT3的表达。我们得出结论，p53与干扰素激活途径之间的相互作用比最初预期的更为复杂，它们之间的协同作用值得进一步研究。此外，我们发现，根据细胞类型和应激条件，p53可上调或下调SOCS1的表达。
