REPRESSION OF ENDOGENOUS P53 TRANSACTIVATION FUNCTION IN HELA CERVICAL-CARCINOMA CELLS BY HUMAN PAPILLOMAVIRUS TYPE-16 E6, HUMAN MDM-2, ANDMUTANT P53

Somatic mutations in the p53 tumor suppressor gene represent the singl e most common genetic alteration observed in human cancers. Interestin gly, the great majority of malignant tumors of the cervix uteri contai n wild-type p53 alleles together with the DNA of specific types of hum an papillomaviruses (HPVs), while the small portion of HPV-negative ce rvical carcinomas often carry alterations in the p53 tumor suppressor gene. Transcriptional activation of yet-undefined cellular regulatory genes has been implicated to play a key role for the tumor-suppressive activity of wild-type p53, as mutant p53 in general has lost the acti vity to stimulate p53-responsive reporter plasmids. The detection of D NA-binding-competent and transcriptionally active p53 protein in HeLa cervical carcinoma cells enabled us to investigate the in vivo effects of putative modulators on endogenous p53 function in cervical cancer cells. We show that the transcriptional stimulatory activity of HeLa c ell p53 is strongly repressed by overexpression of E6 protein from onc ogenic HPV type 16 (HPV16) but is not influenced by low-risk HPV6 E6. Similar to HPV16 E6, cellular oncoproteins such as mutant p53 or the p roduct of the human mdm-2 gene also negatively interfere with p53-medi ated transactivation in HeLa cells. Our findings indicate that, within a cervical cancer cell, the expression of E6 protein from high-risk H PV16, but not from low-risk HPV6, can lead to the same functional cons equences as a mutation of the p53 gene. These results could provide a biochemical basis for the inverse correlation between the presence of HPV sequences and somatic mutations of the p53 gene in cervical carcin omas.