Mishra A, Jana N R
Cellular and Molecular Neuroscience Laboratory, National Brain Research Centre, Manesar, Gurgaon, 122 050, India.
Cell Mol Life Sci. 2008 Feb;65(4):656-66. doi: 10.1007/s00018-007-7476-1.
E6-AP is a founding member of HECT (homologous to E6-AP C terminus) domain subfamily of E3 ubiquitin ligases. It degrades tumor suppressor p53 in association with the E6 oncoprotein of the human papilloma virus. However, there are conflicting reports on its role in the degradation of p53 in the absence of E6 oncoprotein. Here, we studied the role of E6-AP in regulation of p53 in mouse neuro 2a cells. Overexpression of E6-AP in neuro 2a cells increased the ubiquitylation and degradation of p53, which could be prevented upon deletion of HECT domain. E6-AP also directly ubiquitylated p53 in an in vitro ubiquitylation assay. Partial knockdown of E6-AP increased the levels of p53 and p53-dependent transcription. Partial knockdown also increased neuronal cell death, which may be mediated partly via p53. Our result suggests that E6-AP not only enhances the degradation of p53 but also regulates the neuronal cell growth.
E6-AP是E3泛素连接酶HECT（与E6-AP C末端同源）结构域亚家族的创始成员。它与人乳头瘤病毒的E6癌蛋白一起降解肿瘤抑制因子p53。然而，关于其在缺乏E6癌蛋白时在p53降解中的作用存在相互矛盾的报道。在这里，我们研究了E6-AP在小鼠神经2a细胞中对p53的调节作用。在神经2a细胞中过表达E6-AP会增加p53的泛素化和降解，而删除HECT结构域后这种情况可以被阻止。在体外泛素化实验中，E6-AP也直接使p53泛素化。部分敲低E6-AP会增加p53的水平以及p53依赖的转录。部分敲低还会增加神经元细胞死亡，这可能部分是通过p53介导的。我们的结果表明，E6-AP不仅增强p53的降解，还调节神经元细胞生长。
