摘要
程序性细胞死亡因子4(programmed cell death 4, PDCD4)是在研究细胞凋亡机制中克隆出来的新基因.后来发现PDCD4广泛表达于多种组织和器官,但是在多种肿瘤中表达缺失或低表达,恢复PDCD4表达可明显抑制肿瘤的生长或迁移侵袭,是一种新的抑癌基因.进一步研究发现PDCD4不仅发挥抑癌基因的作用,而且参与炎性疾病的发生和发展,它是一把"双刃剑",在不同的疾病模型中表现出促进或抑制的作用,研究表明PDCD4敲除小鼠(Mus musculus)可以有效抵抗实验性自身免疫性脑脊髓炎、1型糖尿病、肥胖及动脉粥样硬化等慢性炎性疾病的发生,而PDCD4敲除后加重LPS(lipopolysaccharide)诱导的急性肝损伤和DSS(Dextran sulfate sodium salt)诱导的急性结肠炎. PDCD4的作用机制尚不完全清楚,目前认为PDCD4对下游靶基因的调控主要通过两种方式:翻译起始因子eIF4A依赖性和非依赖性的方式. eIF4A依赖性方式是指PDCD4通过与eIF4A直接相互作用抑制其解旋酶活性,进而抑制具有特定5′UTR结构m RNA的翻译; eIF4A非依赖方式是指PDCD4可以通过与其他蛋白质(如转录因子)结合,抑制其活性或干扰其磷酸化进而调控靶基因的转录及其下游一系列信号通路.本文对PDCD4的作用和机制进行综述,并对其成为肿瘤和多种疾病治疗的新靶点进行展望.
Programmed cell death 4(PDCD4) is a novel gene obtained during the study of apoptotic mechanisms. It is widely expressed in various tissues and organs of healthy individuals. Its expression is lost or reduced in various tumors, and forced expression can markedly inhibit tumor growth or migration and invasion; therefore, PDCD4 has been regarded as a new tumor suppressor gene.Increasing research has suggested that PDCD4 not only plays an antitumor role but also is involved in inflammatory disease, thereby acting as a double-edged sword by promoting or inhibiting disease development in different models. PDCD4 knockout mice exhibit resistance to the development of experimental autoimmune encephalomyelitis, diabetes, obesity, and atherosclerosis. However,deficiency of PDCD4 aggravates LPS-induced acute liver injury and DSS-induced acute colitis. The mechanism underlying PDCD4’s mode of action remains unclear. Increasing evidence has suggested that PDCD4 regulates downstream target genes via both translation initiation factor eIF4 A-dependent and independent mechanisms. In the eIF4 A-dependent mechanism, PDCD4 inhibits the helicase activity of eIF4 A by directly binding to e IF4 A, thereby inhibiting mRNA translation with a specific 5′UTR structure. In the eIF4 A-independent mechanism, PDCD4 can either bind to other proteins, such as transcription factors, thereby preventing their activation or interfere with protein phosphorylation, thereby regulating downstream signaling pathways. In this review, we will summarize the roles and mechanisms of PDCD4 and its prospects as a new target for the treatment of tumors and various diseases.
作者
贾玉峰
陈晓彤
张利宁
JIA YuFeng;CHEN XiaoTong;ZHANG LiNing(Department of Immunology,School of Basic Medical Sciences,Shandong University,Jinan 250012,China)
出处
《中国科学：生命科学》
CSCD
北大核心
2018年第11期1217-1228,共12页
Scientia Sinica(Vitae)
作者简介
联系人,张利宁 E-mail:zhanglining@sdu.Edu.cn。
