Camus Suzanne, Higgins Maureen, Lane David P, Lain Sonia
Department of Surgery and Molecular Oncology, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
FEBS Lett. 2003 Feb 11;536(1-3):220-4. doi: 10.1016/s0014-5793(03)00054-1.
The human papillomavirus (HPV) protein E6 can promote the ubiquitination of the p53 tumour suppressor in vitro, providing an explanation for the ability of E6 to induce p53 degradation in vivo and contribute to the potential tumorigenic effect of the virus. Instead, in non-infected cells, p53 levels are primarily destabilised by the ubiquitin E3 ligase activity of the Mdm2 protein. Here we have compared the effects of E6 and Mdm2 on p53 ubiquitination in vivo. We show that whereas in the presence of Mdm2 proteasome inhibitors induce the accumulation of ubiquitinated forms of p53, this does not occur in the presence of E6. Accordingly, we confirm that the effect of E6 and p53 is independent of the six C-terminal lysine residues in p53, which have previously been described to play an important role for effective ubiquitination and degradation of 53 mediated by Mdm2. We also show that other yet unidentified residues in p53 are also susceptible to ubiquitination. These results indicate that E6 does not induce ubiquitination of p53 in the same way as Mdm2 in order to promote its degradation, suggesting important differences between the Mdm2 and E6 effects on p53 degradation.
人乳头瘤病毒（HPV）蛋白E6在体外可促进肿瘤抑制因子p53的泛素化，这就解释了E6在体内诱导p53降解的能力，并有助于该病毒潜在的致瘤作用。相反，在未感染的细胞中，p53水平主要因Mdm2蛋白的泛素E3连接酶活性而不稳定。在此，我们比较了E6和Mdm2在体内对p53泛素化的影响。我们发现，在存在Mdm2的情况下，蛋白酶体抑制剂会诱导p53泛素化形式的积累，而在存在E6的情况下则不会发生这种情况。因此，我们证实E6对p53的作用独立于p53的六个C末端赖氨酸残基，此前已描述这些残基在Mdm2介导的p53有效泛素化和降解中起重要作用。我们还表明，p53中的其他尚未确定的残基也易受泛素化影响。这些结果表明，E6不会以与Mdm2相同的方式诱导p53泛素化以促进其降解，这表明Mdm2和E6对p53降解的作用存在重要差异。
