Zimmermann H, Degenkolbe R, Bernard H U, O'Connor M J
Institute of Molecular and Cell Biology, Singapore 117 609, Singapore.
J Virol. 1999 Aug;73(8):6209-19. doi: 10.1128/JVI.73.8.6209-6219.1999.
The transforming proteins of the small DNA tumor viruses, simian virus 40 (SV40), adenovirus, and human papillomavirus (HPV) target a number of identical cellular regulators whose functional abrogation is required for transformation. However, while both adenovirus E1A and SV40 large T transforming properties also depend on the targeting of the transcriptional coactivator CBP/p300, no such interaction has been described for the HPV oncoprotein E6 or E7. Here, we demonstrate that the HPV-16 E6 protein, previously shown to facilitate the degradation of p53 in a complex with E6-associated protein (E6AP), also targets CBP/p300 in an interaction involving the C-terminal zinc finger of E6 and CBP residues 1808 to 1826. Furthermore, this interaction is limited to E6 proteins of high-risk HPVs associated with cervical cancer that have the capacity to repress p53-dependent transcription. An HPV-16 E6 mutant (L50G) that binds CBP/p300, but not E6AP, is still capable of down-regulating p53 transcriptional activity. Thus, HPV E6 proteins possess two distinct mechanisms by which to abrogate p53 function: the repression of p53 transcriptional activity by targeting the p53 coactivator CBP/p300, and the removal of cellular p53 protein through the proteosome degradation pathway.
小型DNA肿瘤病毒（猴病毒40，即SV40、腺病毒和人乳头瘤病毒，即HPV）的转化蛋白作用于许多相同的细胞调节因子，而转化需要这些调节因子的功能被消除。然而，虽然腺病毒E1A和SV40大T抗原的转化特性也依赖于对转录共激活因子CBP/p300的作用，但尚未发现HPV癌蛋白E6或E7存在此类相互作用。在此，我们证明，之前显示能在与E6相关蛋白（E6AP）形成的复合物中促进p53降解的HPV-16 E6蛋白，在涉及E6的C端锌指和CBP的1808至1826位残基的相互作用中，也作用于CBP/p300。此外，这种相互作用仅限于与宫颈癌相关的高危HPV的E6蛋白，这些E6蛋白有能力抑制p53依赖性转录。一种结合CBP/p300但不结合E6AP的HPV-16 E6突变体（L50G），仍然能够下调p53的转录活性。因此，HPV E6蛋白具有两种不同的机制来消除p53的功能：通过作用于p53共激活因子CBP/p300来抑制p53的转录活性，以及通过蛋白酶体降解途径去除细胞中的p53蛋白。
