The phosphoprotein product of p53 is known to suppress cell transformation as well as cell proliferation (Eliyahu et al., 1989; Finlay et al., 1989; Michalowitz et al., 1990). These functions of the p53 protein have come to light from its interaction with the products of certain tumour-promoting genes. The oncogenic proteins of DNA tumour viruses achieve cell transformation by forming complexes with the wild-type phosphoprotein p53 (Lane and Crawford, 1979; Linzer et al., 1979; Sarnow et al., 1982; Lin and Simmons, 1991). The simian virus 40 (SV40) large T antigen has since been shown to block DNA binding by p53 and its function as a transcription factor (Mietz et al., 1992). The adenovirus E1B 55 kDa protein is also able to bind p53 and neutralise it (Sarnow et al, 1982; Kao et al., 1990; Berk and Yew, 1992). The introduction of wild-type p53 into transformed cells is known to block the growth of transformed cells (Baker et al, 1990b; Diller etal., 1990).
The p53 protein is expressed at very low levels in normal cells and tissues and it has a short half-life. However, in cells transformed by SV40 and adenoviruses, much higher levels are detected (Benchimole et al., 1982) and this appears to be due to increased stability and a consequent enhancement of the half-life of the protein. Using a temperature-sensitive mutant of the large T antigen, Oren et al. (1981) showed that this depended upon the functioning of the T antigen. Interaction of p53 with other cellular proteins has also been demonstrated, which may lead to an inactivation and abrogation of its normal function.
It was demonstrated some years ago that human papilloma viruses (HPV), especially HPV 16, 18 and also some other types, are associated with high-grade cervical intraepithelial neoplasia (CIN) and invasive cervical squamous carcinomas. The integration of these viruses in the genome results in increased expression of the proteins known as E6 and E7, and these proteins have the ability to transform cells into the neoplastic state. Immunohistochemical studies have shown co-localisation of p53 phosphoprotein and E6, suggesting an association between them (Liang et al., 1993). It would appear that the E6 protein binds the p53 phosphoprotein (Werness et al, 1990). This requires another cellular factor called the E6-associated protein (E6-AP). This event leads to a rapid degradation of p53 protein, mediated by ubiquitin-dependent proteolysis (Huibregtse etal., 1993). The introduction of a single HPV16-E6 gene causes the immortalisation of cells and sharply reduces p53 protein levels (Band et al., 1991). The E6-E7 fusion proteins will also degrade the retinoblastoma protein (rb) (Scheffner et al., 1991, 1992). Therefore, the concept has emerged that the sequestration of p53 protein by formation of complexes with oncoproteins such as E6 might lead to the development of cervical neoplasia. In HPV-negative carcinomas, inactivation of p53 by mutation or allelic deletion, leading to the abrogation of its normal function of regulation of cell proliferation, can be postulated as a mechanism of tumorigenesis. But this has not been found to be the case. Park et al. (1994) found p53 mutations only in 10% of HPV-negative tumours. There are also other reports that allelic or mutation of this gene is not a frequent event, irrespective of HPV status (Fujita et al., 1992). In contrast, another study has reported that HPV-positive tumours contained p53 mutation in only 8% of the tumours examined whereas four out of nine HPV-negative tumours contained point mutations (Lee et al., 1994). This suggests that tumour development can occur either by mutation of p53 or by neutralisation of wild-type p53 by interaction with HPV proteins. A consensus view is that the formation of p53-E6 complex leads to a sequestration of p53 protein and this prevents it from exercising its normal suppressor function.
There is also the possibility that other oncogenes might be cooperating with HPV in tumour induction. Some experimental studies by DiPaolo et al. (1989) showed that although HPV types are associated with cervical malignancies, transfer of HPV16 orl8 DNA into normal cervical cells caused their immortalisation but did not confer tumorigenicity on them. However, upon sequential transfection of the HPV-immortalised cells with the oncogene H-ras, these cells were able to produce cystic squamous cell carcinomas in immune-deficient mice.
Was this article helpful?