FAILURE OF HPV E6 TO RAPIDLY DEGRADE P53 IN HUMAN HELA X PNET CELL HYBRIDS

The ability of the E6 protein from high risk human papillomaviruses (H PVs) to degrade p53 via the ubiquitin pathway plays a major role in th e development of cervical carcinomas. We have previously generated cel l hybrids between a p53 null peripheral neuroepithelioma (PNET) cell l ine and a cervical carcinoma HeLa cell line which exhibits efficient E 6-mediated degradation of p53. All of the resulting hybrids expressed HPV 18 E6 from the HeLa parent and some of the hybrids additionally ex pressed HPV 16 E6. Surprisingly, in spite of abundant E6 expression, t he hybrids expressed relatively high steady-state levels of the wild-t ype p53 protein. We then examined the hybrids to determine whether oth er components of the E6-mediated degradation pathway were missing or n onfunctional. Specifically, we determined that the E6-associated prote in (E6-AP), essential for E6-mediated degradation, was expressed. We f urther verified that these hybrids had a functional ubiquitination pat hway, which suggests that this phenomenon is not due to a general defe ct in this pathway. We therefore conclude that other unidentified, pos sibly cell-specific factors can play a role in the E6-mediated degrada tive process and may act to inhibit this process.