PML RING suppresses oncogenic transformation by reducing the affinity of eIF4E for mRNA
PML RING suppresses oncogenic transformation by reducing the affinity of eIF4E for mRNA
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DOI：
10.1093/emboj/20.16.4547
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发表时间：
2001-08-15
期刊：
影响因子：
11.4
通讯作者：
Borden, KLB
中科院分区：
文献类型：
--
作者：
Cohen, N;Sharma, M;Borden, KLB
早幼粒细胞白血病蛋白PML组织成核体，介导致癌转化和生长的抑制。PML小体的生化功能尚不清楚，尽管它们参与了几种人类疾病。我们证明真核起始因子4 E（eIF 4E）直接结合PML RING，这是与身体结合和抑制转化所需的结构域。核eIF4E在包括细胞周期蛋白D1在内的转录子的核质转运中发挥作用。目前的研究表明，一些PML需要进化上更古老的eIF4E蛋白与核体结合。此外，PML RING通过显著降低eIF4E对其底物（mRNA的5 ′ m（7）G帽）的亲和力来调节eIF4E活性。我们证明，eIF4E需要帽结合细胞周期蛋白D1 mRNA的运输和随后的转化活性。此外，PML降低eIF4E对m（7）G mRNA帽的亲和力，导致细胞周期蛋白DI蛋白水平降低，从而抑制转化。PML是显示调节核eIF4E功能的第一个因子。这些发现为了解PML的转化抑制活性提供了第一个生化框架。
The promyelocytic leukemia protein PML is organized into nuclear bodies which mediate suppression of oncogenic transformation and of growth. The biochemical functions of PML bodies are unknown, despite their involvement in several human disorders. We demonstrate that eukaryotic initiation factor 4E (eIF4E) directly binds the PML RING, a domain required for association with bodies and for suppression of transformation. Nuclear eIF4E functions in nucleocytoplasmic transport of a subset of transcripts including Cyclin D1. Present studies indicate that some PML requires the evolutionarily older eIF4E protein for association with nuclear bodies. Furthermore, PML RING modulates eIF4E activity by drastically reducing its affinity for its substrate, 5 ' m(7)G cap of mRNA. We demonstrate that eIF4E requires cap binding for transport of Cyclin D1 mRNA and subsequent transformation activity. Additionally, PML reduces the affinity of eIF4E for m(7)G mRNA cap, causing a reduction in Cyclin DI protein levels and consequent transformation inhibition. PML is the first factor shown to modulate nuclear eIF4E function. These findings provide the first biochemical framework for understanding the transformation suppression activity of PML.