Differential localization of oligomeric and monomeric forms of high risk HPV E6 oncoproteins in naturally transformed cell lines and carcinoma tissue.

GARCÍA ALAI, M.M.; DANTUR, K.; SMAL, C.; FERRARI, C.; PITOSSI, F.; PIETRASANTA, L.; TATTI, S.; VIGHI, S.; PRAT GY, G. DE

University of Warwick, Reino Unido

Congreso; Society for General Microbiology 158th Meeting, University of Warwick, Papillomavirus Workshop,; 2006

Human papillomavirus E6 and E7 oncoproteins transform ephithelial cells in various virus linked neoplasias, where the most relevant is cervical cancer in women. HPV E6 and E7 have also been instrumental in elucidating fundamental aspects of p53 and retinoblastoma tumour suppressor cell cycle control, with counterpart activities in various DNA tumour viruses. E7 is a ca100 amino acid acidic protein and E6 is a 150 amino acid basic protein, both with cystein mediated zinc binding motifs but with no biochemical function other than binding reported for them. Given their small size, it is difficult to explain the over 50 protein targets that have been reported for the proteins.  Both proteins readily form large soluble oligomers, indicating that the monomeric or dimeric forms are not the only possible conformations. E7 is an extended dimer, 50 nm spherical oligomers formed upon removal of zinc are regular and we found that they have chaperone holdase activity, which may explain its apparent target promiscuity.  Recombinant high risk E6 oncoproteins refold into oligomers of ~1.2 MDa molecular weight.  Contrary to the monomeric forms, the E6 oligomers are deficient in promoting p53 degradation in vitro.  We detect and localize the endogenous oncoproteins in HPV transformed cell lines for the first time and describe a differential localization for each conformer.