Zhu Ningxi, Gu Lubing, Findley Harry W, Zhou Muxiang
Division of Pediatric Hematology/Oncology/BMT, Emory University School of Medicine, Atlanta, GA, USA.
Biochem Biophys Res Commun. 2005 Oct 7;335(4):1272-9. doi: 10.1016/j.bbrc.2005.08.026.
The eukaryotic initiation factor 4E (eIF4E) plays important roles in transformation and cancer progression. It is frequently overexpressed in malignant cells, one mechanism of which is through transcriptional activation by c-myc. Here, we report that high level of eIF4E expression and its tumorigenicity could be alternatively associated with defects of p53, since we found that induction of wt-p53 repressed eIF4E expression. Gene transfection of p53 inhibited eIF4E promoter activity, while inactivation of p53 either by mutation or by over-expression of MDM2 resulted in stimulation of eIF4E promoter activity. We demonstrated that p53-repression of eIF4E was regulated by c-myc. The wt-p53 can physically bind to c-myc, which inhibited binding of c-myc to eIF4E promoter and c-myc-stimulated promoter activity. These results suggest that the expression of eIF4E is reciprocally regulated by p53 and c-myc, and loss of p53-mediated control over c-myc-dependent transactivation of eIF4E may represent a novel mechanism for eIF4E-mediated neoplastic transformation and cancer progression.
真核生物起始因子4E（eIF4E）在细胞转化和癌症进展中发挥重要作用。它在恶性细胞中经常过度表达，其中一种机制是通过c-myc的转录激活。在此，我们报告eIF4E的高水平表达及其致瘤性可能与p53缺陷相关，因为我们发现野生型p53的诱导可抑制eIF4E表达。p53的基因转染抑制了eIF4E启动子活性，而通过突变或MDM2的过表达使p53失活则导致eIF4E启动子活性增强。我们证明p53对eIF4E的抑制受c-myc调控。野生型p53可与c-myc直接结合，这抑制了c-myc与eIF4E启动子的结合以及c-myc刺激的启动子活性。这些结果表明，eIF4E的表达受p53和c-myc的相互调控，并且p53介导的对c-myc依赖的eIF4E反式激活的控制丧失可能代表了eIF4E介导的肿瘤转化和癌症进展的一种新机制。
