E6AP promotes the degradation of the PML tumor suppressor
E6AP promotes the degradation of the PML tumor suppressor
复制标题
DOI：
10.1038/cdd.2009.31
复制
发表时间：
2009-08-01
影响因子：
12.4
通讯作者：
Haupt, Y.
中科院分区：
文献类型：
--
作者：
Louria-Hayon, I.;Alsheich-Bartok, O.;Haupt, Y.
早幼粒细胞白血病（PML）肿瘤抑制因子对PML核小体（NBs）的形成至关重要。PML和PML- nbs参与了生长抑制、衰老和细胞凋亡的调控。PML在应激信号下被激活，在某些人类癌症中被下调。然而，介导PML稳定性的因素尚不完全清楚。在这里，我们证明了哺乳动物E3连接酶E6AP （HPV e6相关蛋白）的催化活性形式通过促进PML蛋白在蛋白酶体中的降解来减少PML蛋白的半衰期。在体外泛素化实验中，E6AP介导PML的泛素化。E6AP和PML在生理水平上相互作用，并在PML- nbs中共定位。重要的是，PML蛋白在E6AP缺失小鼠的多个器官和细胞类型中表达升高，在淋巴样细胞中表达升高与PML- nbs的数量和强度增加有关。这种PML升高是对DNA损伤的反应。我们的研究结果表明E6AP是PML和PML- nb的重要调节因子。细胞死亡与分化（2009）16,1156-1166；doi: 10.1038 / cdd.2009.31;2009年3月27日在线发布
The promyelocytic leukemia (PML) tumor suppressor is essential for the formation of PML nuclear bodies (NBs). PML and PML-NBs have been implicated in the regulation of growth inhibition, senescence and apoptosis. PML is activated in response to stress signals and is downregulated in certain human cancers. However, the factors mediating PML stability are incompletely understood. Here we demonstrate that a catalytically active form of the mammalian E3 ligase E6AP (HPV E6-associated protein) acts to reduce the half-life of the PML protein by promoting its degradation in the proteasome. E6AP mediates the ubiquitination of PML in an in vitro ubiquitination assay. E6AP and PML interact at physiological levels and colocalize in PML-NBs. Importantly, PML protein expression is elevated in multiple organs and cell types from E6AP null mice and in lymphoid cells is associated with increased number and intensity of PML-NBs. This PML elevation is enhanced in response to DNA damage. Our results identify E6AP as an important regulator of PML and PML-NBs. Cell Death and Differentiation (2009) 16, 1156-1166; doi:10.1038/cdd.2009.31; published online 27 March 2009