Pim David, Thomas Miranda, Banks Lawrence
International Centre for Genetic Engineering and Biotechnology, Area Science Park, Padriciano-99, I-34012, Trieste, Italy.
Oncogene. 2002 Nov 21;21(53):8140-8. doi: 10.1038/sj.onc.1206026.
The ability of HPV E6 oncoproteins to induce the degradation of PDZ domain-containing MAGUK proteins correlates with their malignant potential. We previously showed that the HPV-6 E6 protein, when provided with the PDZ-binding domain from HPV-18 E6, acquires the ability to bind the Discs Large (Dlg) tumour suppressor and target it for degradation. Based on this finding we have extended this analysis to E6 proteins from a variety of different papillomavirus types. Cloning a PDZ-binding sequence onto the C-terminus of E6 proteins derived from low-risk mucosal, and low and high-risk cutaneous papillomavirus types, enables them to bind Dlg and a second MAGUK family member, MAGI-1. This renders the mucosally-derived low-risk chimaeric HPV E6 proteins capable of targeting Dlg for degradation, but they are unable to induce significant levels of degradation of MAGI-1. In contrast, none of the E6 proteins derived from cutaneous papillomavirus types induce significant degradation of either MAGI-1 or Dlg when provided with a PDZ-binding domain. These results demonstrate significant differences, both between mucosal and cutaneous HPV E6 proteins and in the pathways required for Dlg and MAGI-1 degradation.
人乳头瘤病毒E6癌蛋白诱导含PDZ结构域的膜相关鸟苷酸激酶（MAGUK）蛋白降解的能力与其恶性潜能相关。我们之前发现，人乳头瘤病毒6型E6蛋白若带有来自人乳头瘤病毒18型E6的PDZ结合结构域，就能获得结合盘状大蛋白（Dlg）肿瘤抑制因子并使其降解的能力。基于这一发现，我们将此分析扩展至多种不同乳头瘤病毒类型的E6蛋白。在源自低风险黏膜型、低风险和高风险皮肤型乳头瘤病毒的E6蛋白C末端克隆一个PDZ结合序列，可使其结合Dlg和另一个MAGUK家族成员MAGI-1。这使得源自黏膜的低风险嵌合型人乳头瘤病毒E6蛋白能够将Dlg作为降解靶点，但它们无法诱导MAGI-1发生显著程度的降解。相比之下，当带有PDZ结合结构域时，源自皮肤型乳头瘤病毒的E6蛋白均不会诱导MAGI-1或Dlg发生显著降解。这些结果表明，黏膜型和皮肤型人乳头瘤病毒E6蛋白之间以及Dlg和MAGI-1降解所需途径均存在显著差异。
