Koeppel Max, van Heeringen Simon J, Smeenk Leonie, Navis Anna C, Janssen-Megens Eva M, Lohrum Marion
Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands.
Nucleic Acids Res. 2009 Feb;37(2):322-35. doi: 10.1093/nar/gkn940. Epub 2008 Nov 28.
The tumor suppressor p53 contributes to the cellular fate after genotoxic insults, mainly through the regulation of target genes, thereby allowing e.g. repair mechanisms resulting in cell survival or inducing apoptosis. Unresolved so far is the issue, which exact mechanisms lead to one or the other cellular outcome. Here, we describe the interferon regulatory factor-2-binding protein-2 (IRF2BP2) as a new direct target gene of p53, influencing the p53-mediated cellular decision. We show that upregulation of IRF2BP2 after treatment with actinomycin D (Act.D) is dependent on functional p53 in different cell lines. This occurs in parallel with the down-regulation of the interacting partner of IRF2BP2, the interferon regulatory factor-2 (IRF2), which is known to positively influence cell growth. Analyzing the molecular functions of IRF2BP2, it appears to be able to impede on the p53-mediated transactivation of the p21- and the Bax-gene. We show here that overexpressed IRF2BP2 has an impact on the cellular stress response after Act.D treatment and that it diminishes the induction of apoptosis after doxorubicin treatment. Furthermore, the knockdown of IRF2BP2 leads to an upregulation of p21 and faster induction of apoptosis after doxorubicin as well as Act.D treatment.
肿瘤抑制因子p53主要通过调控靶基因，在基因毒性损伤后决定细胞命运，从而使细胞能够采取如通过修复机制实现存活或诱导凋亡等不同途径。目前尚未明确的是，究竟哪些确切机制会导致细胞出现这两种不同的结果。在此，我们将干扰素调节因子2结合蛋白2（IRF2BP2）描述为p53的一个新的直接靶基因，它会影响p53介导的细胞决策。我们发现，放线菌素D（Act.D）处理后IRF2BP2的上调在不同细胞系中均依赖于功能性p53。这一过程与IRF2BP2的相互作用伙伴干扰素调节因子2（IRF2）的下调同时发生，已知IRF2对细胞生长具有正向影响。通过分析IRF2BP2的分子功能，发现它似乎能够抑制p53介导的p21基因和Bax基因的转录激活。我们在此表明，过表达的IRF2BP2对Act.D处理后的细胞应激反应有影响，并且它会减少阿霉素处理后凋亡的诱导。此外，敲低IRF2BP2会导致p21上调，并在阿霉素和Act.D处理后更快地诱导凋亡。
