Nawaz Z, Lonard D M, Smith C L, Lev-Lehman E, Tsai S Y, Tsai M J, O'Malley B W
Department of Cell Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Mol Cell Biol. 1999 Feb;19(2):1182-9. doi: 10.1128/MCB.19.2.1182.
In this study, we found that the E6-associated protein (E6-AP/UBE3A) directly interacts with and coactivates the transcriptional activity of the human progesterone receptor (PR) in a hormone-dependent manner. E6-AP also coactivates the hormone-dependent transcriptional activities of the other members of the nuclear hormone receptor superfamily. Previously, it was shown that E6-AP serves the role of a ubiquitin-protein ligase (E3) in the presence of the E6 protein from human papillomavirus types 16 and 18. Our data show that the ubiquitin-protein ligase function of E6-AP is dispensable for its ability to coactivate nuclear hormone receptors, showing that E6-AP possesses two separable independent functions, as both a coactivator and a ubiquitin-protein ligase. Disruption of the maternal copy of E6-AP is correlated with Angelman syndrome (AS), a genetic neurological disorder characterized by severe mental retardation, seizures, speech impairment, and other symptoms. However, the exact mechanism by which the defective E6-AP gene causes AS remains unknown. To correlate the E6-AP coactivator function and ubiquitin-protein ligase functions with the AS phenotype, we expressed mutant forms of E6-AP isolated from AS patients and assessed the ability of each of these mutant proteins to coactivate PR or provide ubiquitin-protein ligase activity. This analysis revealed that in the majority of the AS patients examined, the ubiquitin-protein ligase function of E6-AP was defective whereas the coactivator function was intact. This finding suggests that the AS phenotype results from a defect in the ubiquitin-proteosome protein degradation pathway.
在本研究中，我们发现E6相关蛋白（E6-AP/UBE3A）以激素依赖的方式直接与人类孕激素受体（PR）相互作用并共激活其转录活性。E6-AP还共激活核激素受体超家族其他成员的激素依赖转录活性。此前研究表明，在人乳头瘤病毒16型和18型的E6蛋白存在时，E6-AP发挥泛素蛋白连接酶（E3）的作用。我们的数据表明，E6-AP的泛素蛋白连接酶功能对于其共激活核激素受体的能力并非必需，这表明E6-AP具有两种可分离的独立功能，即作为共激活因子和泛素蛋白连接酶。母本E6-AP基因的破坏与天使综合征（AS）相关，AS是一种遗传性神经疾病，其特征为严重智力迟钝、癫痫发作、语言障碍及其他症状。然而，有缺陷的E6-AP基因导致AS的确切机制仍不清楚。为了将E6-AP共激活因子功能和泛素蛋白连接酶功能与AS表型相关联，我们表达了从AS患者中分离出的E6-AP突变体形式，并评估了每种突变蛋白共激活PR或提供泛素蛋白连接酶活性的能力。该分析表明，在所检测的大多数AS患者中，E6-AP的泛素蛋白连接酶功能有缺陷，而共激活因子功能完好。这一发现提示AS表型是由泛素-蛋白酶体蛋白降解途径缺陷所致。
