通过抑制MDM2表达和DNA损伤协同激活p53
Synergistic activation of p53 by inhibition of MDM2 expression and DNA damage.
作者信息
Chen L, Agrawal S, Zhou W, Zhang R, Chen J
机构信息
Department of Microbiology, Louisiana State University Medical Center, Stanley S. Scott Cancer Center, New Orleans, LA 70112, USA.
出版信息
Proc Natl Acad Sci U S A. 1998 Jan 6;95(1):195-200. doi: 10.1073/pnas.95.1.195.
The MDM2 oncogene encodes an inhibitor of the p53 tumor suppressor protein that regulates p53 in a negative feedback loop. MDM2 gene amplification and overexpression occur in several types of tumors and are often associated with poor prognosis. An MDM2 antisense phosphorothioate oligodeoxynucleotide has been identified that effectively inhibits MDM2 expression in tumor cells containing MDM2 gene amplifications. Antisense inhibition of MDM2 is associated with a decrease in MDM2-p53 complex formation, increase in p53-inducible gene expression, increase in p53 transcriptional activity, and apoptosis. Significantly, inhibition of MDM2 expression enhances the activation of p53 by a DNA-damaging cancer chemotherapy agent in a synergistic fashion. Therefore, the MDM2 negative feedback pathway is an important limiting factor in DNA damage-induced p53 activation. MDM2 antisense oligonucleotides may be useful as antitumor agents alone or as enhancers of other conventional DNA-damaging drugs.
MDM2癌基因编码一种p53肿瘤抑制蛋白的抑制剂，该抑制剂在负反馈回路中调节p53。MDM2基因扩增和过表达发生在多种类型的肿瘤中，且常与不良预后相关。已鉴定出一种MDM2反义硫代磷酸酯寡脱氧核苷酸，它能有效抑制含有MDM2基因扩增的肿瘤细胞中的MDM2表达。对MDM2的反义抑制与MDM2-p53复合物形成减少、p53诱导型基因表达增加、p53转录活性增加以及细胞凋亡有关。重要的是，抑制MDM2表达能以协同方式增强DNA损伤性癌症化疗药物对p53的激活作用。因此，MDM2负反馈途径是DNA损伤诱导的p53激活中的一个重要限制因素。MDM2反义寡核苷酸单独作为抗肿瘤药物或作为其他传统DNA损伤药物的增强剂可能会有用。
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