Retinoblastoma (Rb) protein upregulates expression of the Ifi202 gene encoding an interferon-inducible negative regulator of cell growth.
Retinoblastoma (Rb) protein upregulates expression of the Ifi202 gene encoding an interferon-inducible negative regulator of cell growth.
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视网膜母细胞瘤 (Rb) 蛋白上调 Ifi202 基因的表达，该基因编码干扰素诱导的细胞生长负调节因子。
DOI：
10.1038/sj.onc.1206780
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发表时间：
2003
期刊：
影响因子：
8
通讯作者：
Choubey,Divaker
中科院分区：
文献类型：
--
作者：
Xin,Hong;Pramanik,Rocky;Choubey,Divaker
研究表明，p202的异位表达，干扰素（IFN）诱导的视网膜母细胞瘤（Rb）结合蛋白，在培养的细胞延缓细胞增殖和调节细胞存活。与p202在细胞周期调节中的作用一致，在撤除血清生长因子后，停滞在细胞周期的G 0/G 1期的细胞中p202的水平增加。然而，p202在细胞生长停滞中的作用仍有待确定。此外，仍不清楚在细胞生长停滞期间p202的水平如何上调。在这里，我们报告Rb上调Ifi 202基因的表达。我们发现，基础以及干扰素诱导的p202水平显着高于野生型（Rb+/+）小鼠胚胎成纤维细胞（MEFs）比同基因Rb−/− MEFs。与Rb对Ifi 202基因的调控一致，功能性Rb的表达而不是其口袋突变体的表达刺激了Ifi 202基因5′调控区驱动的报告基因的活性。重要的是，Rb的刺激部分依赖于Ifi 202基因5′调控区的JunD/AP-1 DNA结合位点。此外，野生型（JunD+/+）中p202的基础水平显著高于同基因JunD−/− MEFs。此外，我们发现p202表达的增加增强了Rb介导的细胞生长抑制，并且p202的Rb结合基序（LxCxE）的突变显著降低了细胞存活率。总之，我们的观察支持Rb/JunD对Ifi 202基因的转录激活可能对细胞生长和存活的调节很重要的想法。
Studies have indicated that ectopic expression of p202, an interferon (IFN)-inducible retinoblastoma (Rb)-binding protein, in cultured cells retards cell proliferation and modulates cell survival. Consistent with a role of p202 in cell cycle regulation, levels of p202 increase in cells arrested in the G 0/G 1 phase of cell cycle after withdrawal of serum growth factors. However, a role for p202 in cell growth arrest remains to be defined. Moreover, it remains unclear how levels of p202 are upregulated during the cell growth arrest. Here, we report that Rb upregulates expression of Ifi202 gene. We found that basal as well as IFN-induced levels of p202 were significantly higher in wild-type (Rb+/+) mouse embryonic fibroblasts (MEFs) than isogenic Rb−/− MEFs. Consistent with the regulation of Ifi202 gene by Rb, expression of functional Rb, but not a pocket mutant of it, stimulated the activity of a reporter whose expression was driven by the 5′-regulatory region of Ifi202 gene. Importantly, the stimulation by Rb was dependent, in part, on a JunD/AP-1 DNA-binding site present in the 5′-regulatory region of the Ifi202 gene. Moreover, basal levels of p202 were significantly higher in wild-type (JunD+/+) than isogenic JunD−/− MEFs. Additionally, we found that increased expression of p202 potentiated the Rb-mediated inhibition of cell growth and mutations in the Rb-binding motif (LxCxE) of p202 significantly reduced cell survival. Together, our observations support the idea that the transcriptional activation of Ifi202 gene by Rb/JunD may be important for the regulation of cell growth and survival.