Human papillomavirus E6 proteins bind p53 in vivo and abrogate p53-mediated repression of transcription.

Abstract

The transforming proteins of DNA tumor viruses SV40, adenovirus and human papillomaviruses (HPV) bind the retinoblastoma and p53 cell cycle regulatory proteins. While the binding of SV40 large T antigen and the adenovirus E1B 55 kDa protein results in the stabilization of the p53 protein, the binding of HPV16 and 18 E6 results in enhanced degradation in vitro. To explore the effect of viral proteins on p53 stability in vivo, we have examined cell lines immortalized in tissue culture by HPV18 E6 and E7 or SV40 large T antigen, as well as cell lines derived from cervical neoplasias. The half‐life of the p53 protein in non‐transformed human foreskin keratinocytes in culture was found to be approximately 3 h while in cell lines immortalized by E6 and E7, p53 protein half‐lives ranged from 2.8 h to less than 1 h. Since equivalent levels of E6 were found in these cells, the range in p53 levels observed was not a result of variability in amounts of E6. In keratinocyte lines immortalized by E7 alone, the p53 half‐life was found to be similar to that in non‐transformed cells; however, it decreased to approximately 1 h following supertransfection of an E6 gene. These observations are consistent with an interaction of E6 and p53 in vivo resulting in reductions in the stability of p53 ranging between 2‐ and 4‐fold. We also observed that the expression of various TATA containing promoters was repressed in transient assays by co‐transfection with plasmids expressing the wild‐type p53 gene.(ABSTRACT TRUNCATED AT 250 WORDS)

Twenty years of p53 research: structural and functional aspects of the p53 protein

“…For instance the product of the mdm2 oncogene, which binds and is believed to mask the activation domain of p53, is overexpressed in certain tumours, resulting in the abrogation of p53 function, accompanied by the proteolytic degradation of p53, mediated by the ubiquitin pathway Oliner et al, 1992Oliner et al, , 1993Midgley and Lane, 1997). Additional data showed that p53 may down-regulate the expression from a number of other promoters including those of the c-fos, c-jun, c-myc, b-actin, hsc-70, IL-6 genes (Ginsberg et al, 1991;Lechner et al, 1992;Ko and Prives, 1996). In contrast to the p53-mediated transactivation, the p53-mediated transrepression does not involve an interaction between p53 and DNA.…”

`Gain of function' phenotype of tumor-derived mutant p53 requires the oligomerization/nonsequence-specific nucleic acid-binding domain

“…Extracts were normalized for protein concentration and assayed for CAT enzyme activity (Ludes-Meyers et al, 1996). Because wild-type p53 inhibits and mutant p53 activates di erent promoters to varying extents Ginsberg et al, 1991;Lechner et al, 1992;Santhanam et al, 1991;Subler et al, 1992), it was not possible to use an internal control such as pSVbGal or RSVbGal (Ludes-Meyers et al, 1996). A similar situation has been recognized for SV40 T antigen-mediated regulation of promoters (Gruda et al, 1993).…”

Oncolytic viral therapies

“…Deletion of the first element, the E1B 55 kDa fragment, enables replication of Onyx 015 in cells with a defective p53 pathway (cancer cells) 2,46,47 and minimizes replication in cells with a functional p53 pathway (normal cells). Some controversy exists on whether or not the sole mechanism by which Onyx 015 has selective replication capacity in malignant cells is related to p53.…”